37 results on '"M Albert Basson"'
Search Results
2. The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration
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M. Albert Basson, Andrea Streit, Elysia James, Ravindra Singh Prajapati, Ruth Moon, and Mohi Ahmed
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Male ,Cell type ,QH301-705.5 ,Medicine (miscellaneous) ,Sensory system ,Degeneration (medical) ,Stimulus (physiology) ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Chromodomain ,Mice ,Stress, Physiological ,Hair Cells, Auditory ,medicine ,otorhinolaryngologic diseases ,Animals ,Humans ,Biology (General) ,Cochlear Nerve ,Disease model ,medicine.disease ,Embryonic stem cell ,Cell biology ,DNA-Binding Proteins ,Phenotype ,Mutation ,Sensorineural hearing loss ,Female ,sense organs ,General Agricultural and Biological Sciences ,Haploinsufficiency ,Neuroscience - Abstract
Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms., To improve our understanding of the mechanisms that protect hair cells in the ear from stress-induced death, Ahmed et al delete the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons and hair cells in mice. They observe sensorineural hearing loss and demonstrate that CHD7 controls the expression of stress pathway components, which could help to explain how CHD7 haploinsufficiency causes changes in the ear associated with CHARGE syndrome.
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- 2021
3. Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development
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Angela Caruso, Olivier Brock, Cathy Fernandes, Caterina Michetti, Kimberley L. H. Riegman, Conor Mohan, Philipp Suetterlin, M. Albert Basson, Shaun Hurley, Romy Evans, Robert Ellingford, Jacob Ellegood, Alessio Delogu, Fabrizio Rudari, Jason P. Lerch, and Maria Luisa Scattoni
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p53 ,Apoptosis ,Autism ,CHD8 ,Chromatin ,Conditional knockout ,Cortex ,Gene expression ,Hypomorph ,Intermediate progenitor ,Mouse ,Neural progenitor ,Proliferation ,TBR2 ,Animals ,Animals, Newborn ,Autistic Disorder ,Behavior, Animal ,Brain ,Cell Proliferation ,DNA-Binding Proteins ,Disease Models, Animal ,Female ,Gene Expression Regulation, Developmental ,Mice, Transgenic ,Phenotype ,Pregnancy ,Stem Cells ,Tumor Suppressor Protein p53 ,lcsh:RC346-429 ,Transgenic ,Mice ,0302 clinical medicine ,Conditional gene knockout ,Developmental ,0303 health sciences ,education.field_of_study ,Neocortex ,Human brain ,Cell biology ,Psychiatry and Mental health ,medicine.anatomical_structure ,Haploinsufficiency ,Population ,Biology ,03 medical and health sciences ,Developmental Neuroscience ,medicine ,Progenitor cell ,education ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Progenitor ,Behavior ,Animal ,Research ,Newborn ,Gene Expression Regulation ,Disease Models ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
BackgroundCHD8haploinsufficiency causes autism and macrocephaly with high penetrance in the human population.Chd8heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficientChd8mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.MethodsTo examine the possibility that certain phenotypes may only appear at sub-heterozygousChd8levels in the mouse, we created an allelic series ofChd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate.ResultsMildChd8hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. SevereChd8hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion ofChd8in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex.LimitationsOur findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice.ConclusionsTogether, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth.Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.
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- 2021
4. Engrailed controls epaxial-hypaxial muscle innervation and the establishment of vertebrate three-dimensional mobility
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Pascal Maire, M. Albert Basson, Ashish K. Maurya, Susanne Dietrich, Louise Y. Cheng, Frank Schubert, Erika Cristina Jorge, Philip W. Ingham, and Mohi Ahmed
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locomotion and mobility ,0301 basic medicine ,Body Patterning ,dorsal ramus ,Muscle Development ,spinal nerves ,Myoblasts ,Mice ,Myotome ,Myocyte ,Zebrafish ,axon guidance ,Gene Expression Regulation, Developmental ,Vertebrate ,Anatomy ,Cell biology ,Phenotype ,medicine.anatomical_structure ,Somites ,Movement ,chicken ,vertebrate development and evolution ,Biology ,03 medical and health sciences ,Developmental Neuroscience ,biology.animal ,medicine ,Animals ,Muscle, Skeletal ,Molecular Biology ,mouse ,Ecology, Evolution, Behavior and Systematics ,Homeodomain Proteins ,epaxial-hypaxial muscle ,Engrailed gene ,Cell Biology ,zebrafish ,biology.organism_classification ,Axons ,engrailed ,Somite ,030104 developmental biology ,Animals, Newborn ,muscle innervation ,Axon guidance ,ventral ramus ,Chickens ,Biomarkers ,Transcription Factors ,Developmental Biology - Abstract
Chordates are characterised by contractile muscle on either side of the body that promotes movement by side-to-side undulation. In the lineage leading to modern jawed vertebrates (crown group gnathostomes), this system was refined: body muscle became segregated into distinct dorsal (epaxial) and ventral (hypaxial) components that are separately innervated by the medial and hypaxial motors column, respectively, via the dorsal and ventral ramus of the spinal nerves. This allows full three-dimensional mobility, which in turn was a key factor in their evolutionary success. How the new gnathostome system is established during embryogenesis and how it may have evolved in the ancestors of modern vertebrates is not known.Vertebrate Engrailed genes have a peculiar expression pattern as they temporarily demarcate a central domain of the developing musculature at the epaxial-hypaxial boundary. Moreover, they are the only genes known with this particular expression pattern. The aim of this study was to investigate whether Engrailed genes control epaxial-hypaxial muscle development and innervation.Investigating chick, mouse and zebrafish as major gnathostome model organisms, we found that the Engrailed expression domain was associated with the establishment of the epaxial-hypaxial boundary of muscle in all three species. Moreover, the outgrowing epaxial and hypaxial nerves orientated themselves with respect to this Engrailed domain. In the chicken, loss and gain of Engrailed function changed epaxial-hypaxial somite patterning. Importantly, in all animals studied, loss and gain of Engrailed function severely disrupted the pathfinding of the spinal motor axons, suggesting that Engrailed plays an evolutionarily conserved role in the separate innervation of vertebrate epaxial-hypaxial muscle.
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- 2017
5. Autism-linked CHD gene expression patterns during development predict multi-organ disease phenotypes
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Sahrunizam Kasah, M. Albert Basson, and Christopher Oddy
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0301 basic medicine ,Histology ,Neurogenesis ,Biology ,medicine.disease_cause ,Chromodomain ,03 medical and health sciences ,Mice ,Intellectual disability ,medicine ,Gene family ,Animals ,Autistic Disorder ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Exome sequencing ,Genetics ,Mutation ,Cell Biology ,Original Articles ,medicine.disease ,Embryo, Mammalian ,DNA-Binding Proteins ,030104 developmental biology ,Phenotype ,CHD2 ,Autism ,Anatomy ,Haploinsufficiency ,Transcriptome ,Developmental Biology - Abstract
Recent large-scale exome sequencing studies have identified mutations in several members of the CHD (Chromodomain Helicase DNA-binding protein) gene family in neurodevelopmental disorders. Mutations in the CHD2 gene have been linked to developmental delay, intellectual disability, autism and seizures, CHD8 mutations to autism and intellectual disability, whereas haploinsufficiency of CHD7 is associated with executive dysfunction and intellectual disability. In addition to these neurodevelopmental features, a wide range of other developmental defects are associated with mutants of these genes, especially with regards to CHD7 haploinsufficiency, which is the primary cause of CHARGE syndrome. Whilst the developmental expression of CHD7 has been reported previously, limited information on the expression of CHD2 and CHD8 during development is available. Here, we compare the expression patterns of all three genes during mouse development directly. We find high, widespread expression of these genes at early stages of development that gradually becomes restricted during later developmental stages. Chd2 and Chd8 are widely expressed in the developing central nervous system (CNS) at all stages of development, with moderate expression remaining in the neocortex, hippocampus, olfactory bulb and cerebellum of the postnatal brain. Similarly, Chd7 expression is seen throughout the CNS during late embryogenesis and early postnatal development, with strong enrichment in the cerebellum, but displays low expression in the cortex and neurogenic niches in early life. In addition to expression in the brain, novel sites of Chd2 and Chd8 expression are reported. These findings suggest additional roles for these genes in organogenesis and predict that mutation of these genes may predispose individuals to a range of other, non-neurological developmental defects.
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- 2018
6. Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia
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Ophir D. Klein, Gerald R. Cunha, M. Albert Basson, Saunders T. Ching, and Laurence S. Baskin
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Male ,Time Factors ,Fibroblast growth factor ,Medical and Health Sciences ,Transgenic ,Mice ,0302 clinical medicine ,FGF ,Developmental ,In Situ Hybridization ,Regulation of gene expression ,Hypospadias ,0303 health sciences ,Intracellular Signaling Peptides and Proteins ,Adaptor Proteins ,Gene Expression Regulation, Developmental ,Biological Sciences ,Protein-Serine-Threonine Kinases ,Immunohistochemistry ,Cell biology ,Female ,Signal transduction ,Signal Transduction ,Urologic Diseases ,Cell signaling ,MAP Kinase Signaling System ,1.1 Normal biological development and functioning ,Genital tubercle ,Sprouty ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Biology ,Article ,03 medical and health sciences ,Urethra ,Underpinning research ,Genetics ,Animals ,Genitalia ,Urothelium ,Molecular Biology ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,030304 developmental biology ,Signal Transducing ,Membrane Proteins ,Cell Biology ,Phosphoproteins ,Molecular biology ,Fibroblast Growth Factors ,Gene Expression Regulation ,SPRY2 ,Mutation ,Gene Deletion ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Development of the mammalian external genitalia is controlled by a network of signaling molecules and transcription factors. Because FGF signaling plays a central role in this complicated morphogenetic process, we investigated the role of Sprouty genes, which are important intracellular modulators of FGF signaling, during embryonic development of the external genitalia in mice. We found that Sprouty genes are expressed by the urethral epithelium during embryogenesis, and that they have a critical function during urethral canalization and fusion. Development of the genital tubercle (GT), the anlage of the prepuce and glans penis in males and glans clitoris in females, was severely affected in male embryos carrying null alleles of both Spry1 and Spry2. In Spry1(-/-);Spry2(-/-) embryos, the internal tubular urethra was absent, and urothelial morphology and organization was abnormal. These effects were due, in part, to elevated levels of epithelial cell proliferation in Spry1(-/-);Spry2(-/-) embryos. Despite changes in overall organization, terminal differentiation of the urothelium was not significantly affected. Characterization of the molecular pathways that regulate normal GT development confirmed that deletion of Sprouty genes leads to elevated FGF signaling, whereas levels of signaling in other cascades were largely preserved. Together, these results show that levels of FGF signaling must be tightly regulated during embryonic development of the external genitalia in mice, and that this regulation is mediated in part through the activity of Sprouty gene products.
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- 2014
7. Sprouty genes are essential for the normal development of epibranchial ganglia in the mouse embryo
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Heiko Lickert, M. Albert Basson, and Subreena Simrick
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animal structures ,Fibroblast Growth Factor 8 ,Genotype ,Sprouty ,Haploinsufficiency ,Protein Serine-Threonine Kinases ,Biology ,Fibroblast growth factor ,FGF8 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Ganglia, Sensory ,Animals ,Epibranchial placodes ,Molecular Biology ,Glossopharyngeal Nerve ,In Situ Hybridization ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Cranial nerves ,Intracellular Signaling Peptides and Proteins ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Neural crest ,Vagus Nerve ,Genomes and Developmental Control ,Cell Biology ,Anatomy ,Phosphoproteins ,Immunohistochemistry ,Facial nerve ,Cell biology ,Vagus nerve ,Facial Nerve ,Branchial Region ,Neural Crest ,Glossopharyngeal nerve ,embryonic structures ,030217 neurology & neurosurgery ,Signal Transduction ,Developmental Biology - Abstract
Fibroblast growth factor (FGF) signalling has important roles in the development of the embryonic pharyngeal (branchial) arches, but its effects on innervation of the arches and associated structures have not been studied extensively. We investigated the consequences of deleting two receptor tyrosine kinase (RTK) antagonists of the Sprouty (Spry) gene family on the early development of the branchial nerves. The morphology of the facial, glossopharyngeal and vagus nerves are abnormal in Spry1−/−;Spry2−/− embryos. We identify specific defects in the epibranchial placodes and neural crest, which contribute sensory neurons and glia to these nerves. A dissection of the tissue-specific roles of these genes in branchial nerve development shows that Sprouty gene deletion in the pharyngeal epithelia can affect both placode formation and neural crest fate. However, epithelial-specific gene deletion only results in defects in the facial nerve and not the glossopharyngeal and vagus nerves, suggesting that the facial nerve is most sensitive to perturbations in RTK signalling. Reducing the Fgf8 gene dosage only partially rescued defects in the glossopharyngeal nerve and was not sufficient to rescue facial nerve defects, suggesting that FGF8 is functionally redundant with other RTK ligands during facial nerve development., Highlights ► Sprouty gene deletion in mouse embryos cause multiple defects in epibranchial ganglia. ► Both epibranchial placodes and neural crest cells are affected. ► Sprouty gene function is required in the pharyngeal ectoderm and endoderm. ► Hyperactive FGF8 signalling is in part responsible for these defects.
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- 2011
8. Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development
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Yaopan Mao, Katherine M. Morgan, Steve Allen, Philippa Francis-West, Sana Zakaria, M. Albert Basson, Tian Yu, Joanna Mulvaney, and Kenneth D. Irvine
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DCHS1 ,Mutation ,Cadherin ,Organogenesis ,Mutant ,Cell Polarity ,Biology ,Cadherins ,Kidney ,medicine.disease_cause ,Phenotype ,Mice, Mutant Strains ,Cell biology ,Mice ,Hippo signaling ,Cell polarity ,medicine ,Animals ,Growth and Development ,Signal transduction ,Molecular Biology ,Research Articles ,Signal Transduction ,Developmental Biology - Abstract
The Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs.
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- 2011
9. Expression of fibroblast growth factors (Fgfs) in murine tooth development
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Yoko Otsuka-Tanaka, Paul T. Sharpe, M. Albert Basson, Thantrira Porntaveetus, Anne M. Moon, and Atsushi Ohazama
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Molar ,Pathology ,medicine.medical_specialty ,Histology ,FGF20 ,Mesenchyme ,Cervical loop ,Cell Biology ,FGF18 ,Biology ,Fibroblast growth factor ,Cell biology ,stomatognathic diseases ,medicine.anatomical_structure ,stomatognathic system ,Incisor ,medicine ,Anatomy ,Ameloblast ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Developmental Biology - Abstract
Fgf signalling is known to play critical roles in tooth development. Twenty-two Fgf ligands have been identified in mammals, but expression of only 10 in molars and three in the incisor loop stem cell region have been documented in murine tooth development. Our understanding of Fgf signalling in tooth development thus remains incomplete and we therefore carried out comparative in situ hybridisation analysis of unexamined Fgf ligands (eight in molars and 15 in cervical loops of incisors; Fgf11–Fgf14 were excluded from this analysis because they are not secreted and do not activate Fgf receptors) during tooth development. To identify where Fgf signalling is activated, we also examined the expression of Etv4 and Etv5, considered to be transcriptional targets of the Fgf signalling pathway. In molar tooth development, the expression of Fgf15 and Fgf20 was restricted to the primary enamel knots, whereas Etv4 and Etv5 were expressed in cells surrounding the primary enamel knots. Fgf20 expression was observed in the secondary enamel knots, whereas Fgf15 showed localised expression in the adjacent mesenchyme. Fgf16, Etv4 and Etv5 were strongly expressed in the ameloblasts of molars. In the incisor cervical loop stem cell region, Fgf17, Fgf18, Etv4 and Etv5 showed a restricted expression pattern. These molecules thus show dynamic temporo-spatial expression in murine tooth development. We also analysed teeth in Fgf15−/− and Fgf15−/−;Fgf8+/− mutant mice. Neither mutant showed significant abnormalities in tooth development, indicating likely functional redundancy.
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- 2011
10. Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum
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Diego Echevarria, Yuichiro Yaguchi, M. Albert Basson, Tian Yu, and Salvador Martinez
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Cell type ,Cerebellum ,Mouse ,Blotting, Western ,Sprouty ,Nerve Tissue Proteins ,Protein Serine-Threonine Kinases ,Fibroblast growth factor ,SHH ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Granule cell ,In Situ Nick-End Labeling ,medicine ,Animals ,FGF ,Hedgehog Proteins ,Sonic hedgehog ,Molecular Biology ,In Situ Hybridization ,Research Articles ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,biology ,Histological Techniques ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Phosphoproteins ,Immunohistochemistry ,Molecular biology ,Mice, Mutant Strains ,Hedgehog signaling pathway ,3. Good health ,Cell biology ,Fibroblast Growth Factors ,Phenotype ,medicine.anatomical_structure ,CXCL3 ,Cerebellar vermis ,biology.protein ,030217 neurology & neurosurgery ,Signal Transduction ,Developmental Biology - Abstract
12 p., 8 figures and references., Fibroblast growth factors (FGFs) and regulators of the FGF signalling pathway are expressed in several cell types within the cerebellum throughout its development. Although much is known about the function of this pathway during the establishment of the cerebellar territory during early embryogenesis, the role of this pathway during later developmental stages is still poorly understood. Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse. Simultaneous deletion of more than one of these genes resulted in a number of defects, including mediolateral expansion of the cerebellar vermis, reduced thickness of the granule cell layer and abnormal foliation. Analysis of cerebellar development revealed that the anterior cerebellar neuroepithelium in the early embryonic cerebellum was expanded and that granule cell proliferation during late embryogenesis and early postnatal development was reduced. We show that the granule cell proliferation deficit correlated with reduced sonic hedgehog (SHH) expression and signalling. A reduction in Fgfr1 dosage during development rescued these defects, confirming that the abnormalities are due to excess FGF signalling. Our data indicate that sprouty acts both cell autonomously in granule cell precursors and non-cell autonomously to regulate granule cell number. Taken together, our data demonstrate that FGF signalling levels have to be tightly controlled throughout cerebellar development in order to maintain the normal development of multiple cell types., This work was supported by grants from the Wellcome Trust to M.A.B. (080470 and 091475), the European commission (HEALTH-F4-2010-261492) and the Spanish MICINN (SAF2008-01004, BFU2008-00588 and CSD2007-00023) to D.E. and S.M.
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- 2011
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11. Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C
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Charuta Ambardekar, Simge Akbulut, Barbara Canciani, Steven E. Quatela, Priya Aggarwal, Mark Phillips, Alagarsamy Lakku Reddi, Tomas Vilimas, Jacqueline M. Mason, M. Albert Basson, Samuel L. Collins, Jonathan D. Licht, Jonathan D. Powell, Matthew Lovatt, Laura M. Hix, and Marianne K.H. Kim
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Antigens, Differentiation, T-Lymphocyte ,endocrine system ,Transcription, Genetic ,T-Lymphocytes ,Intracellular Space ,Receptors, Antigen, T-Cell ,Inositol 1,4,5-Trisphosphate ,Protein Serine-Threonine Kinases ,Biology ,Receptor tyrosine kinase ,Diglycerides ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Animals ,Immunoprecipitation ,Lectins, C-Type ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Calcium signaling ,Diacylglycerol kinase ,0303 health sciences ,Phospholipase C ,Phospholipase C gamma ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Signal transducing adaptor protein ,Articles ,Cell Biology ,Phosphoproteins ,Molecular biology ,Signaling ,Cell biology ,Enzyme Activation ,030220 oncology & carcinogenesis ,SPRY2 ,NIH 3T3 Cells ,ras Proteins ,biology.protein ,Phosphorylation ,Calcium ,Mitogen-Activated Protein Kinases ,Biomarkers ,Protein Binding ,Proto-oncogene tyrosine-protein kinase Src - Abstract
PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors., Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling; however, their exact mechanism of action remains incompletely understood. We identified phosphatidylinositol-specific phospholipase C (PLC)-γ as a partner of the Spry1 and Spry2 proteins. Spry–PLCγ interaction was dependent on the Src homology 2 domain of PLCγ and a conserved N-terminal tyrosine residue in Spry1 and Spry2. Overexpression of Spry1 and Spry2 was associated with decreased PLCγ phosphorylation and decreased PLCγ activity as measured by production of inositol (1,4,5)-triphosphate (IP3) and diacylglycerol, whereas cells deficient for Spry1 or Spry1, -2, and -4 showed increased production of IP3 at baseline and further increased in response to growth factor signals. Overexpression of Spry 1 or Spry2 or small-interfering RNA-mediated knockdown of PLCγ1 or PLCγ2 abrogated the activity of a calcium-dependent reporter gene, suggesting that Spry inhibited calcium-mediated signaling downstream of PLCγ. Furthermore, Spry overexpression in T-cells, which are highly dependent on PLCγ activity and calcium signaling, blocked T-cell receptor-mediated calcium release. Accordingly, cultured T-cells from Spry1 gene knockout mice showed increased proliferation in response to T-cell receptor stimulation. These data highlight an important action of Spry, which may allow these proteins to influence signaling through multiple receptors.
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- 2010
12. Fibroblast growth factor (FGF) gene expression in the developing cerebellum suggests multiple roles for FGF signaling during cerebellar morphogenesis and development
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Mohi Ahmed, Tian Yu, Mary Berry, Ivor Mason, Yuichiro Yaguchi, and M. Albert Basson
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Cerebellum ,Cell type ,Morphogenesis ,Mice, Transgenic ,Biology ,Ligands ,Bioinformatics ,Fibroblast growth factor ,FGF and mesoderm formation ,Mice ,Pregnancy ,Gene expression ,medicine ,Animals ,Receptor ,In Situ Hybridization ,Cell Proliferation ,Embryogenesis ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Receptors, Fibroblast Growth Factor ,Cell biology ,Fibroblast Growth Factors ,medicine.anatomical_structure ,nervous system ,Female ,Signal Transduction ,Developmental Biology - Abstract
The cerebellum is derived from the anterior-most segment of the embryonic hindbrain, rhombomere 1 (r1). Previous studies have shown that the early development and patterning of r1 requires fibroblast growth factor (FGF) signaling. However, many of the developmental processes that shape cerebellar morphogenesis take place later in embryonic development and during the first 2 weeks of postnatal life in the mouse. Here, we present a more comprehensive analysis of the expression patterns of genes encoding FGF receptors and secreted FGF ligands during these later stages of cerebellar development. We show that these genes are expressed in multiple cell types in the developing cerebellum, in an astonishing array of distinct patterns. These data suggest that FGF signaling functions throughout cerebellar development to regulate many processes that shape the formation of a functional cerebellum. Developmental Dynamics, 2009. © 2009 Wiley-Liss, Inc.
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- 2009
13. Itch−/−αβ and γδ T cells independently contribute to autoimmunity in Itchy mice
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Valentino Parravicini, Anne-Christine Field, Rose Zamoyska, M. Albert Basson, and Peter Tomlinson
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biology ,T cell ,Immunology ,Cell Biology ,Hematology ,Immunoglobulin E ,medicine.disease_cause ,Biochemistry ,Cell biology ,Ubiquitin ligase ,Autoimmunity ,Haematopoiesis ,medicine.anatomical_structure ,Antigen ,Ubiquitin ,biology.protein ,medicine ,Receptor - Abstract
E3 ubiquitin ligases determine which intracellular proteins are targets of the ubiquitin conjugation pathway and thus play a key role in determining the half-life, subcellular localization and/or activation status of their target proteins. Itchy mice lack the E3 ligase, Itch, and show dysregulation of T lymphocytes and the induction of a lethal autoimmune inflammatory condition. Itch is widely expressed in hematopoietic and nonhematopoietic cells, and we demonstrate that disease is transferred exclusively by hematopoietic cells. Moreover, distinct manifestations of the autoimmune inflammatory phenotype are contributed by discrete populations of lymphocytes. The presence of Itch-deficient αβ T cells drives expansion of peritoneal B1b cells and elevated IgM levels, which correlate with itching and pathology. In contrast, Itch−/− interleukin-4–producing γδ T cells, even in the absence of αβ T cells, are associated with elevated levels of IgE and an inflammatory condition. These data indicate that disruption of an E3 ubiquitin ligase in αβ T cells can subvert a B-cell subpopulation, which normally functions to control particular microbial pathogens in a T-independent manner, to contribute to autoimmunity. In addition, disruption of Itch in innate γδ T cells can influence autoimmune pathology and might therefore require distinct therapeutic intervention.
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- 2008
14. Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1
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Patricia D. Wilson, Judy Watson-Johnson, M. Albert Basson, Jonathan D. Licht, Reena Shakya, Deborah Hyink, Ivor Mason, Simge Akbulut, and Frank Costantini
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medicine.medical_specialty ,Kidney development ,Renal hypoplasia ,Kidney ,Receptor tyrosine kinase ,Mice ,03 medical and health sciences ,Cystic kidney disease ,0302 clinical medicine ,Neurotrophic factors ,Internal medicine ,Glial cell line-derived neurotrophic factor ,medicine ,Branching morphogenesis ,Animals ,Glial Cell Line-Derived Neurotrophic Factor ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Hyperplasia ,biology ,urogenital system ,Membrane Proteins ,Cell Biology ,Kidney Diseases, Cystic ,Phosphoproteins ,medicine.disease ,GDNF ,Epithelium ,Cell biology ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Sprouty1 ,nervous system ,Ureteric bud ,biology.protein ,Ureteric epithelium ,Ureteric bud formation ,Ureter ,Urothelium ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear. Here we show that the absence of the receptor tyrosine kinase antagonist Sprouty1 (Spry1) results in irregular branching morphogenesis characterized by both increased number and size of ureteric bud tips. Deletion of Spry1 specifically in the epithelium is associated with increased epithelial Wnt11 expression as well as increased mesenchymal Gdnf expression. We propose that Spry1 regulates a Gdnf/Ret/Wnt11-positive feedback loop that coordinates mesenchymal–epithelial dialogue during branching morphogenesis. Genetic experiments indicate that the positive (GDNF) and inhibitory (Sprouty1) signals have to be finely balanced throughout renal development to prevent hypoplasia or cystic hyperplasia. Epithelial cysts develop in Spry1-deficient kidneys that share several molecular characteristics with those observed in human disease, suggesting that Spry1 null mice may be useful animal models for cystic hyperplasia.
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- 2006
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15. Sprouty1 Is a Critical Regulator of GDNF/RET-Mediated Kidney Induction
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Patricia D. Wilson, Thomas L. Carroll, Frank Costantini, Judy Watson-Johnson, M. Albert Basson, Simge Akbulut, Reena Shakya, Ruth Simon, Isabelle Gross, Ivor Mason, Thomas Lufkin, Andrew P. McMahon, Jonathan D. Licht, and Gail R. Martin
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Male ,Gene Dosage ,Regulator ,Kidney development ,Kidney ,Receptor tyrosine kinase ,Mice ,0302 clinical medicine ,Glial cell line-derived neurotrophic factor ,Receptor ,Embryonic Induction ,Mice, Knockout ,0303 health sciences ,biology ,Gene Expression Regulation, Developmental ,Wolffian Ducts ,Cell biology ,Phenotype ,medicine.anatomical_structure ,Female ,Signal Transduction ,medicine.medical_specialty ,Cell signaling ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,General Biochemistry, Genetics and Molecular Biology ,Feedback ,03 medical and health sciences ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Animals ,Humans ,Glial Cell Line-Derived Neurotrophic Factor ,Nerve Growth Factors ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Base Sequence ,urogenital system ,Proto-Oncogene Proteins c-ret ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,DNA ,Cell Biology ,Phosphoproteins ,Mice, Inbred C57BL ,Endocrinology ,SPRY2 ,biology.protein ,Ureter ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Summary Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1) , causes defects in kidney development in mice. Spry1 −/− embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.
- Published
- 2005
16. Author response: Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome
- Author
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Monica Ty Wong, Timothy Bowler, Danny Reinberg, Tian Yu, Linda C. Meiners, Katrin Danielsen, M. Albert Basson, Conny M. A. van Ravenswaaij-Arts, and Peter J. Scambler
- Subjects
CHARGE syndrome ,medicine ,Cerebellar vermis hypoplasia ,Biology ,Homeotic gene ,medicine.disease ,Fibroblast growth factor ,Cell biology - Published
- 2013
17. Early Growth Response (Egr)-1 Gene Induction in the Thymus in Response to TCR Ligation During Early Steps in Positive Selection Is Not Required for CD8 Lineage Commitment
- Author
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Victor L. J. Tybulewicz, Giuseppe Legname, Tim Wilson, M. Albert Basson, Peter Tomlinson, Rose Zamoyska, and Nitza Sarner
- Subjects
Transcriptional Activation ,MAP Kinase Signaling System ,Immunology ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,Thymus Gland ,CD8-Positive T-Lymphocytes ,Biology ,Ligands ,Major histocompatibility complex ,Immediate-Early Proteins ,Mice ,Organ Culture Techniques ,Settore BIO/10 - Biochimica ,Animals ,Immunology and Allergy ,Cell Lineage ,Kinase activity ,Protein kinase A ,Transcription factor ,Early Growth Response Protein 1 ,Kinase ,T-cell receptor ,Cell Differentiation ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,body regions ,Thymocyte ,Gene Expression Regulation ,ras Proteins ,biology.protein ,Cancer research ,hormones, hormone substitutes, and hormone antagonists ,CD8 ,Protein Binding ,Transcription Factors - Abstract
The early growth response gene 1 (Egr-1) is induced during positive selection in the thymus and has been implicated in the differentiation of CD4+ thymocytes. Here, we show that signals that specifically direct CD8 lineage commitment also induce Egr-1 DNA-binding activity in the nucleus. However, we find that pharmacological inhibition of mitogen-activated protein kinase/extracellular signal-related kinase kinase activity potently inhibits Egr-1 DNA-binding function at concentrations that promote differentiation of CD8+ thymocytes, suggesting Egr-1 activity is not essential for CD8 commitment. To further determine the role of Egr-1 in thymocyte development, we compare steady-state Egr-1 DNA-binding activity in thymocytes from mice with defined defects in positive selection. The data indicate that the appearance of functional Egr-1 is downstream of signals induced by TCR/MHC engagement, whereas it is less sensitive to alterations in Lck-mediated signals, and does not correlate directly with proficient positive selection. Egr-1 is one of the earliest transcription factors induced upon TCR ligation on immature thymocytes, and plays a potential role in the transcription of genes involved in thymocyte selection.
- Published
- 2000
18. Greatly reduced efficiency of both positive and negative selection of thymocytes in CD45 tyrosine phosphatase-deficient mice
- Author
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Rose Zamoyska, Martin R Turner, P. S. Costello, P. Joseph Mee, Victor L. J. Tybulewicz, and M. Albert Basson
- Subjects
Transgene ,Immunology ,T-cell receptor ,Regulator ,hemic and immune systems ,chemical and pharmacologic phenomena ,Stimulation ,Protein tyrosine phosphatase ,Biology ,Cell biology ,Negative selection ,mental disorders ,T cell selection ,Immunology and Allergy ,Signal transduction ,psychological phenomena and processes - Abstract
The T cell repertoire is shaped by positive and negative selection of thymocytes. TCRmediated signals that determine these selection processes are only partly understood. The CD45 tyrosine phosphatase has been shown to be important for signal transduction through the TCR, but there has been disagreement about whether CD45 is a positive or negative regulator of TCR signaling. Using CD45-deficient mice expressing transgenic TCR, we show that in the absence of CD45 there is a large increase in the thresholds of TCR stimulation required for both positive and negative selection. Our results conclusively demonstrate that in double-positive thymocytes CD45 is a positive regulator of the TCR signals that drive thymic selection events.
- Published
- 1999
19. Sprouty1 Haploinsufficiency Prevents Renal Agenesis in a Model of Fraser Syndrome
- Author
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Peter J. Scambler, Jolanta E. Pitera, M. Albert Basson, and Adrian S. Woolf
- Subjects
medicine.medical_specialty ,Kidney development ,Mice, Transgenic ,Haploinsufficiency ,Fibroblast growth factor ,Brief Communication ,Kidney ,Receptor tyrosine kinase ,Mice ,Internal medicine ,medicine ,Animals ,Humans ,Fraser syndrome ,Renal agenesis ,Adaptor Proteins, Signal Transducing ,Extracellular Matrix Proteins ,FGF10 ,biology ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,General Medicine ,medicine.disease ,Phosphoproteins ,Mice, Mutant Strains ,Cell biology ,Bilateral Renal Agenesis ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Nephrology ,Ureteric bud ,biology.protein ,Fraser Syndrome ,Signal Transduction - Abstract
Deficiency of the extracellular matrix molecule FRAS1, normally expressed by the ureteric bud, leads to bilateral renal agenesis in humans with Fraser syndrome and blebbed ( Fras1 bl/bl ) mice. The metanephric mesenchyme of these mutants fails to express sufficient Gdnf , which activates receptor tyrosine kinase (RTK) signalling, contributing to the phenotype. To determine whether modulating RTK signalling may overcome the abnormal nephrogenesis characteristic of Fraser syndrome, we introduced a single null Sprouty1 allele into Fras1 bl/bl mice, thereby reducing the ureteric bud9s expression of this anti-branching molecule and antagonist of RTK signalling. This prevented renal agenesis in Fras1 bl/bl mice, permitting kidney development and postnatal survival. We found that fibroblast growth factor (FGF) signalling contributed to this genetic rescue, and exogenous FGF10 rescued defects in Fras1 bl/bl rudiments in vitro . Whereas wild-type metanephroi expressed FRAS1 and the related proteins FREM1 and FREM2, FRAS1 was absent and the other proteins were downregulated in rescued kidneys, consistent with a reciprocally stabilized FRAS1/FREM1/FREM2 complex. In addition to contributing to knowledge regarding events during nephrogenesis, the demonstrated rescue of renal agenesis in a model of a human genetic disease raises the possibility that enhancing growth factor signaling might be a therapeutic approach to ameliorate this devastating malformation.
- Published
- 2012
20. Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis
- Author
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Abigail L. Jackson, Julie Gordon, M. Albert Basson, Heiko Lickert, Jennifer R. Gardiner, and Nancy R. Manley
- Subjects
medicine.medical_specialty ,Pharyngeal pouch ,Organogenesis ,Thymus Gland ,Biology ,Fibroblast growth factor ,Fgf ,Sprouty ,Thymus ,Parathyroid ,Pharyngeal Pouch ,Endoderm ,Mouse ,Parathyroid Glands ,Mice ,FGF8 ,stomatognathic system ,Parathyroid hypoplasia ,Internal medicine ,medicine ,Animals ,Primordium ,Molecular Biology ,In Situ Hybridization ,Research Articles ,Gene Expression Regulation, Developmental ,Immunohistochemistry ,Cell biology ,Fibroblast Growth Factors ,stomatognathic diseases ,Endocrinology ,medicine.anatomical_structure ,embryonic structures ,Pouch ,Developmental Biology ,Signal Transduction - Abstract
The thymus and parathyroid glands are derived from the third pharyngeal pouch endoderm. The mechanisms that establish distinct molecular domains in the third pouch and control the subsequent separation of these organ primordia from the pharynx are poorly understood. Here, we report that mouse embryos that lack two FGF feedback antagonists, Spry1 and Spry2, display parathyroid and thymus hypoplasia and a failure of these organ primordia to completely separate from the pharynx. We show that FGF ligands and downstream reporter genes are expressed in highly regionalised patterns in the third pouch and that sprouty gene deletion results in upregulated FGF signalling throughout the pouch endoderm. As a consequence, the initiation of markers of parathyroid and thymus fate is altered. In addition, a normal apoptotic programme that is associated with the separation of the primordia from the pharynx is disrupted, resulting in the maintenance of a thymus-pharynx attachment and a subsequent inability of the thymus to migrate to its appropriate position above the heart. We demonstrate that the sprouty genes function in the pharyngeal endoderm itself to control these processes and that the defects in sprouty-deficient mutants are, at least in part, due to hyper-responsiveness to Fgf8. Finally, we provide evidence to suggest that parathyroid hypoplasia in these mutants is due to early gene expression defects in the third pouch, whereas thymus hypoplasia is caused by reduced proliferation of thymic epithelial cells in the thymus primordium.
- Published
- 2012
21. The aged niche disrupts muscle stem cell quiescence
- Author
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Andrew S. Brack, Joe V. Chakkalakal, Kieran M. Jones, and M. Albert Basson
- Subjects
Aging ,Time Factors ,Satellite Cells, Skeletal Muscle ,Cellular differentiation ,Cell Count ,Biology ,Fibroblast growth factor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Myocyte ,Animals ,Homeostasis ,Stem Cell Niche ,Muscle, Skeletal ,Mitosis ,Cellular Senescence ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,Muscle Cells ,Multidisciplinary ,Cell Cycle ,Membrane Proteins ,PAX7 Transcription Factor ,Cell Differentiation ,Cell cycle ,Flow Cytometry ,Phosphoproteins ,Research Highlight ,Cell biology ,Mice, Inbred C57BL ,Fibroblast Growth Factor 2 ,Stem cell ,Cell aging ,Developmental biology ,030217 neurology & neurosurgery ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction - Abstract
The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function. The expression of fibroblast growth factor in aged muscle fibre, the muscle stem cell niche, is shown to cause satellite cells to lose the capacity for self-renewal, and is thus an age-dependent change that directly influences stem cell quiescence and function. The efficiency of stem-cell maintenance declines with age, but it is not clear whether the stem-cell niche itself plays a part in this decline. Here, Andrew Brack and colleagues report that as mice age, the skeletal-muscle niche becomes more mitogenic — meaning more cells undergo mitosis and differentiation — and less capable of maintaining the quiescence of the skeletal-muscle stem cells. This results in the loss of capacity for stem-cell self-renewal. The protein FGF2 is a key mitogenic factor in the aged niche, although a small number of muscle stem cells express SPRY1, an inhibitor of FGF signalling, and maintain some quiescence in aged skeletal-muscle fibres.
- Published
- 2011
22. Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate
- Author
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Amel Gritli-Linde, Thantrira Porntaveetus, Martyn T. Cobourne, Shigeru Kondo, Paul T. Sharpe, Andrew D. Economou, Atsushi Ohazama, M. Albert Basson, and Jeremy B. Green
- Subjects
animal structures ,Direct evidence ,Fibroblast growth factor ,Models, Biological ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,Animals ,Computer Simulation ,Hedgehog Proteins ,Sonic hedgehog ,In Situ Hybridization ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,biology ,Rugae ,Palate ,Gene Expression Regulation, Developmental ,Anatomy ,Mice, Mutant Strains ,Cell biology ,Fibroblast Growth Factors ,Developmental genetics ,embryonic structures ,biology.protein ,Developmental physiology ,Microdissection ,030217 neurology & neurosurgery - Abstract
We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.
- Published
- 2011
23. Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration
- Author
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M. Albert Basson, Charles Keller, Kelly L. Shea, Jonathan D. Licht, Vincent S. LaPorta, Andrew S. Brack, and Wanyi Xiang
- Subjects
Satellite Cells, Skeletal Muscle ,Skeletal Muscle ,Cellular differentiation ,Cells ,Cell ,Mice, Transgenic ,Apoptosis ,Biology ,Medical and Health Sciences ,Article ,Transgenic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,medicine ,Myocyte ,Animals ,Regeneration ,Homeostasis ,Cell Lineage ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,Cultured ,Signal Transducing ,Skeletal muscle ,Adaptor Proteins ,Membrane Proteins ,PAX7 Transcription Factor ,Cell Differentiation ,Cell Biology ,Cell cycle ,Biological Sciences ,musculoskeletal system ,Phosphoproteins ,Cellular Reprogramming ,STEMCELL ,Cell biology ,Transplantation ,Satellite Cells ,Adult Stem Cells ,medicine.anatomical_structure ,Molecular Medicine ,Stem cell ,030217 neurology & neurosurgery ,Adult stem cell ,Developmental Biology - Abstract
Summary Satellite cells are a heterogeneous population of skeletal muscle specific stem cells capable of self-renewal and differentiation after transplantation. Whether quiescent satellite cells can self-renew and contribute to muscle fiber repair in their endogenous environment in normal regenerating muscle has remained unknown. The transcription factor Pax7 is expressed in satellite cells and is critical for establishing the adult satellite cell pool. Using a temporally-inducible genetic lineage tracing approach (Pax7-CreERtm; R26R-lacZ) to fate-map adult satellite cells, we show that in response to injury quiescent adult Pax7+ cells enter the cell cycle; a subpopulation return to quiescence to fully replenish the satellite cell compartment and the others contribute to de novo muscle fiber formation. We demonstrate that Sprouty1 (Spry1), an inhibitor of receptor tyrosine kinase signaling, is robustly expressed in quiescent Pax7+ satellite cells in uninjured adult muscle, down-regulated in proliferating myogenic cells in injured muscles, and re-induced as Pax7+ cells return to quiescence in regenerated muscles. We show through deletion of Spry1 specifically in cycling adult Pax7+ satellite cells, that Spry1 is required for the return to quiescence and homeostasis of the self-renewing Pax7+ satellite cell pool during repair. Satellite cells unable to return to quiescence succumb to apoptosis leading to a diminished self-renewing Pax7-derived satellite cell pool. Our results define a novel role for Spry1 in adult stem cell biology and tissue repair.
- Published
- 2010
24. 06-P038 Great vessel development requires dizygous expression of Chd7 and Tbx1 in pharyngeal ectoderm
- Author
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M. Albert Basson, Karen McCue, Victoria Randall, Charles Shaw-Smith, Peter J. Scambler, Francesca Vitelli, Catherine Roberts, Vanessa Kyriakopoulou, Elizabeth Illingworth, Koenraad Devriendt, Katrina Prescott, and Subreena Simrick
- Subjects
TBX1 ,Embryology ,medicine.anatomical_structure ,Expression (architecture) ,Great vessels ,medicine ,Ectoderm ,Biology ,Cell biology ,Developmental Biology - Published
- 2009
- Full Text
- View/download PDF
25. Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm
- Author
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William Andrews, Elizabeth Illingworth, Kelly Lammerts van Bueren, M. Albert Basson, Vanessa Kyriakopoulou, Amelie Calmont, James F. Martin, Sarah Ivins, Irinna Papangeli, Peter J. Scambler, and Anne M. Moon
- Subjects
TBX1 ,Ectoderm ,Nerve Tissue Proteins ,Biology ,Mice ,Cell Movement ,medicine ,Animals ,Sonic hedgehog ,Receptors, Immunologic ,GBX2 ,Molecular Biology ,Body Patterning ,Glycoproteins ,Homeodomain Proteins ,Mice, Knockout ,Cardiac neural crest cells ,Neural crest ,Heart ,Arteries ,biochemical phenomena, metabolism, and nutrition ,Embryo, Mammalian ,Surface ectoderm ,Cell biology ,medicine.anatomical_structure ,Branchial Region ,Neural Crest ,Immunology ,embryonic structures ,biology.protein ,Development and Disease ,T-Box Domain Proteins ,Pharyngeal arch ,Developmental Biology ,Signal Transduction - Abstract
Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such knowledge can help to identify new genes involved in cardiovascular disease. The transcription factor Tbx1 plays a vital role in PAA development and is a major contributor to cardiovascular disease associated with DiGeorge syndrome. In this report, we used various genetic approaches to reveal part of a signalling network by which Tbx1 controls PAA development in mice. We investigated the crucial role played by the homeobox-containing transcription factor Gbx2 downstream of Tbx1. We found that PAA formation requires the pharyngeal surface ectoderm as a key signalling centre from which Gbx2, in response to Tbx1, triggers essential directional cues to the adjacent cardiac neural crest cells (cNCCs) en route to the caudal PAAs. Abrogation of this signal generates cNCC patterning defects leading to PAA abnormalities. Finally, we showed that the Slit/Robo signalling pathway is activated during cNCC migration and that components of this pathway are affected in Gbx2 and Tbx1 mutant embryos at the time of PAA development. We propose that the spatiotemporal control of this tightly orchestrated network of genes participates in crucial aspects of PAA development.
- Published
- 2009
26. Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development
- Author
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Ivor Mason, M. Albert Basson, Diego Echevarria, Anamaria Sudarov, Christina P. Ahn, Salvador Martinez, Alexandra L. Joyner, and Gail R. Martin
- Subjects
medicine.medical_specialty ,Cerebellum ,Cerebellum formation ,Embryonic Development ,Biology ,Fibroblast growth factor ,FGF and mesoderm formation ,Article ,Midbrain ,Mice ,FGF8 ,Mesencephalon ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Cell Death ,Integrases ,Embryogenesis ,Gene Expression Regulation, Developmental ,Embryo, Mammalian ,Cell biology ,Fibroblast Growth Factors ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Signal transduction ,Developmental Biology ,Signal Transduction - Abstract
Prospective midbrain and cerebellum formation are coordinated by FGF ligands produced by the isthmic organizer. Previous studies have suggested that midbrain and cerebellum development require different levels of FGF signaling. However, little is known about the extent to which specific regions within these two parts of the brain differ in their requirement for FGF signaling during embryogenesis. Here, we have explored the effects of inhibiting FGF signaling within the embryonic mouse midbrain (mesencephalon) and cerebellum (rhombomere 1) by misexpressing sprouty2 (Spry2) from an early stage. We show that such Spry2 misexpression moderately reduces FGF signaling, and that this reduction causes cell death in the anterior mesencephalon, the region furthest from the source of FGF ligands. Interestingly, the remaining mesencephalon cells develop into anterior midbrain, indicating that a low level of FGF signaling is sufficient to promote only anterior midbrain development. Spry2 misexpression also affects development of the vermis, the part of the cerebellum that spans the midline. We found that, whereas misexpression of Spry2 alone caused loss of the anterior vermis, reducing FGF signaling further, by decreasing Fgf8 gene dose, resulted in loss of the entire vermis. Our data suggest that cell death is not responsible for vermis loss, but rather that it fails to develop because reducing FGF signaling perturbs the balance between vermis and roof plate development in rhombomere 1. We suggest a molecular explanation for this phenomenon by providing evidence that FGF signaling functions to inhibit the BMP signaling that promotes roof plate development., This work was supported by grants from the Wellcome Trust (080470) to M.A.B. and (072111) to M.A.B. and I.M., by the Medical Research Council and a Leverhulme Trust Fellowship to I.M., by the EU research program (LSHG-CT-2004-512003 and MEIF-CT-2006-025154), the Spanish Science Program (MEC BFU2005-09085, RD06/0011/0012), the ELA Foundation Research and TV3 LA (MARATO-062232) to D.E. and S.M., and by the National Institutes of Health (R01 HD050767) to A.L.J. and (R01 CA78711) to G.R.M.
- Published
- 2008
27. An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisors
- Author
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Gail R. Martin, David B. Lyons, Guive Balooch, M. Albert Basson, Renata Peterkova, Miroslav Peterka, Grayson W. Marshall, Ophir D. Klein, and Tomas Boran
- Subjects
medicine.medical_specialty ,Mesoderm ,Cellular differentiation ,Gene Dosage ,Cervical loop ,Nerve Tissue Proteins ,Biology ,Protein Serine-Threonine Kinases ,Fibroblast growth factor ,Models, Biological ,Receptor tyrosine kinase ,Epithelium ,Article ,Mice ,stomatognathic system ,Internal medicine ,medicine ,Ameloblasts ,Animals ,Hedgehog Proteins ,Dental Enamel ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Stem Cells ,Intracellular Signaling Peptides and Proteins ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Cell Differentiation ,Cell biology ,Up-Regulation ,Fibroblast Growth Factors ,Incisor ,stomatognathic diseases ,Endocrinology ,medicine.anatomical_structure ,Phenotype ,Organ Specificity ,biology.protein ,Signal transduction ,Stem cell ,Ameloblast ,Developmental Biology ,Signal Transduction - Abstract
Rodent incisors grow throughout adult life, but are prevented from becoming excessively long by constant abrasion, which is facilitated by the absence of enamel on one side of the incisor. Here we report that loss-of-function of sprouty genes, which encode antagonists of receptor tyrosine kinase signaling,leads to bilateral enamel deposition, thus impeding incisor abrasion and resulting in unchecked tooth elongation. We demonstrate that sprouty genes function to ensure that enamel-producing ameloblasts are generated on only one side of the tooth by inhibiting the formation of ectopic ameloblasts from self-renewing stem cells, and that they do so by preventing the establishment of an epithelial-mesenchymal FGF signaling loop. Interestingly, although inactivation of Spry4 alone initiates ectopic ameloblast formation in the embryo, the dosage of another sprouty gene must also be reduced to sustain it after birth. These data reveal that the generation of differentiated progeny from a particular stem cell population can be differently regulated in the embryo and adult.
- Published
- 2007
28. Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling
- Author
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Jonathan D. Licht, M. Albert Basson, Debra J. Morrison, and Jacqueline M. Mason
- Subjects
Regulation of gene expression ,Feedback, Physiological ,Epidermal Growth Factor ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,Cell Biology ,Biology ,Receptor tyrosine kinase ,Cell biology ,Multicellular organism ,Cell Transformation, Neoplastic ,SPRY2 ,ROR1 ,biology.protein ,Animals ,Humans ,Genes, Tumor Suppressor ,Amino Acid Sequence ,Signal transduction ,Gene ,Function (biology) ,Signal Transduction - Abstract
Receptor tyrosine kinases (RTKs) control a wide variety of processes in multicellular organisms, including proliferation, differentiation, migration and survival. Their activity is tightly controlled through the coordinated action of both positive and negative regulators that function at multiple levels of the signal transduction cascade, and at different time points within the growth-factor-induced response. When this process goes awry, the outcome can be developmental defects and malignancy. Sprouty (Spry) proteins represent a major class of ligand-inducible inhibitors of RTK-dependent signaling pathways. New biochemical and genetic evidence indicates specific roles of the Spry genes in development and multiple modes of action of the Spry proteins in regulation of the RTK-induced response.
- Published
- 2005
29. Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region
- Author
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M. Albert Basson, Siew-Lan Ang, Wei Lin, Jonathan D. Licht, Andrée Dierich, Naihe Jing, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
- Subjects
MESH: Signal Transduction ,MESH: Mice, Mutant Strains ,Mutant ,Fibroblast growth factor ,Embryo Culture Techniques ,MESH: Genotype ,Mice ,Tissue culture ,0302 clinical medicine ,Endocrinology ,MESH: Gene Expression Regulation, Developmental ,MESH: Animals ,MESH: Proteins ,MESH: Nerve Tissue Proteins ,Cloning, Molecular ,GBX2 ,In Situ Hybridization ,0303 health sciences ,Electroporation ,Intracellular Signaling Peptides and Proteins ,Gene Expression Regulation, Developmental ,MESH: Embryo Culture Techniques ,embryonic structures ,MESH: Membrane Proteins ,MESH: Fibroblast Growth Factors ,Signal Transduction ,animal structures ,Genotype ,Nerve Tissue Proteins ,Hindbrain ,MESH: Zebrafish Proteins ,Protein Serine-Threonine Kinases ,Biology ,03 medical and health sciences ,MESH: In Situ Hybridization ,MESH: Homeodomain Proteins ,Genetics ,Animals ,MESH: Cloning, Molecular ,MESH: Electroporation ,MESH: Mice ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Homeodomain Proteins ,Wild type ,Membrane Proteins ,Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,Zebrafish Proteins ,Embryonic stem cell ,Molecular biology ,Mice, Mutant Strains ,Fibroblast Growth Factors ,MESH: Brain Stem ,030217 neurology & neurosurgery ,Brain Stem - Abstract
Sef and Sprouty proteins function as feedback antagonists of fibroblast growth factor (Fgf) signaling in zebrafish embryos. To study the role of Sef in mice, we generated Sef homozygous mutant animals. These animals are viable and show normal expression of mid-hindbrain genes at embryonic days 8.5 and 9.5. To investigate the possibility of functional synergism between Sef and Sprouty proteins, we electroporated Sprouty2(Y55A), which functions in a dominant-negative manner in tissue culture cells into the mid-hindbrain region of wildtype and Sef mutant embryos. The expression pattern of Gbx2, a downstream target of Fgf signaling, was expanded or shifted in electroporated embryos, and this effect was significantly enhanced in the Sef mutant background. Altogether, our results demonstrate that Sef and Sproutys function synergistically to regulate Gbx2 expression in the anterior hindbrain. genesis 41:110-115, 2005. (c) 2005 Wiley-Liss, Inc.
- Published
- 2005
30. The CD4/CD8 lineage decision: integration of signalling pathways
- Author
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Rose Zamoyska and M. Albert Basson
- Subjects
CD4-Positive T-Lymphocytes ,Lineage (genetic) ,T cell ,Immunology ,Down-Regulation ,Receptors, Cell Surface ,Thymus Gland ,Biology ,CD8-Positive T-Lymphocytes ,medicine ,Animals ,Humans ,Lineage commitment ,Receptors, Notch ,Membrane Proteins ,Cell Differentiation ,Cell biology ,Thymocyte ,medicine.anatomical_structure ,Signalling ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Signal intensity ,Signalling pathways ,CD8 ,Signal Transduction ,Transcription Factors - Abstract
An immature CD4 + CD8 + thymocyte can differentiate into a functionally specialized CD4 + or CD8 + T cell. The molecular mechanisms underlying this CD4/CD8 lineage choice are poorly understood. Recent evidence suggests that thymocytes are sensitive to subtle variations in signal intensity and that lineage choice might be the consequence of the integration of signals emanating from multiple pathways.
- Published
- 2000
31. Fgf signaling during cerebellar morphogenesis
- Author
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Tian Yu, Ivor Mason, Yuichiro Yaguchi, Mary Gait, and M. Albert Basson
- Subjects
Morphogenesis ,Cell Biology ,Biology ,Fibroblast growth factor ,Molecular Biology ,FGF and mesoderm formation ,Cell biology ,Developmental Biology - Published
- 2008
- Full Text
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32. Fibroblast growth factor signaling controls development of the cerebellar vermis by inhibiting signals permissive for roofplate formation in anterior rhombomere 1
- Author
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Salvador Martinez, Alexandra L. Joyner, George Minowada, Diego Echevarria, Anamaria Sudarov, Christina Peterson, John O. Mason, and M. Albert Basson
- Subjects
0303 health sciences ,medicine.medical_specialty ,Fibroblast growth factor receptor 2 ,Cell Biology ,Biology ,Rhombomere 1 ,Fibroblast growth factor ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Cerebellar vermis ,Permissive ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology ,Developmental Biology - Published
- 2007
- Full Text
- View/download PDF
33. Signaling in Cell Differentiation and Morphogenesis
- Author
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M. Albert Basson
- Subjects
Cell signaling ,Zygote ,Cellular differentiation ,Morphogenesis ,Embryonic Development ,Cell Differentiation ,Biology ,Cell fate determination ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Animals ,Signal transduction ,Developmental biology ,Organism ,Signal Transduction ,Concepts - Abstract
All the information to make a complete, fully functional living organism is encoded within the genome of the fertilized oocyte. How is this genetic code translated into the vast array of cellular behaviors that unfold during the course of embryonic development, as the zygote slowly morphs into a new organism? Studies over the last 30 years or so have shown that many of these cellular processes are driven by secreted or membrane-bound signaling molecules. Elucidating how the genetic code is translated into instructions or signals during embryogenesis, how signals are generated at the correct time and place and at the appropriate level, and finally, how these instructions are interpreted and put into action, are some of the central questions of developmental biology. Our understanding of the causes of congenital malformations and disease has improved substantially with the rapid advances in our knowledge of signaling pathways and their regulation during development. In this article, I review some of the signaling pathways that play essential roles during embryonic development. These examples show some of the mechanisms used by cells to receive and interpret developmental signals. I also discuss how signaling pathways downstream from these signals are regulated and how they induce specific cellular responses that ultimately affect cell fate and morphogenesis.
- Published
- 2012
34. The control of inner ear morphogenesis by Sprouty and Tbx1 genes in mouse models of 22q11.2 deletion syndrome
- Author
-
Katherine Shim, M. Albert Basson, Bernice E. Morrow, Jennifer R. Gardiner, Yuichiro Yaguchi, and Tian Yu
- Subjects
TBX1 ,Genetics ,animal structures ,embryonic structures ,Deletion syndrome ,Cell Biology ,Biology ,Molecular Biology ,Gene ,Inner ear morphogenesis ,Developmental Biology - Published
- 2010
35. Sprouty genes function as negative regulators of the FGF signalling pathway during cerebellar development
- Author
-
Robert J. Wechsler-Reya, Salvador Martinez, M. Albert Basson, Tian Yu, Diego Echevarria, and Yuichiro Yaguchi
- Subjects
nervous system ,Cell Biology ,Biology ,Fibroblast growth factor ,Molecular Biology ,Gene ,Suppressor of cytokine signalling ,Function (biology) ,Hedgehog signaling pathway ,Developmental Biology ,Cell biology - Published
- 2010
36. 13-P142 The role of Fibroblast growth factor (Fgf) signalling in thymus and parathyroid organogenesis
- Author
-
Julie Gordon, M. Albert Basson, Jennifer R. Gardiner, and Nancy R. Manley
- Subjects
Fibroblast growth factor 23 ,Embryology ,Fibroblast growth factor receptor ,Fibroblast growth factor receptor 2 ,Fibroblast growth factor receptor 1 ,Fibroblast growth factor receptor 4 ,Fibroblast growth factor receptor 3 ,FGF1 ,Biology ,Fibroblast growth factor ,Developmental Biology ,Cell biology - Published
- 2009
37. Molecular requirements for lineage commitment in the thymus - Antibody-mediated receptor engagements reveal a central role for lck in lineage decisions
- Author
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P. Joe Mee, M. Albert Basson, Victor L. J. Tybulewicz, Rose Zamoyska, and Ursula Bommhardt
- Subjects
Genetics ,CD4-Positive T-Lymphocytes ,Cellular immunity ,Lineage (genetic) ,biology ,CD3 ,Cellular differentiation ,Immunology ,T-cell receptor ,Receptors, Antigen, T-Cell ,Cell Differentiation ,Thymus Gland ,CD8-Positive T-Lymphocytes ,Models, Biological ,Cell biology ,Thymocyte ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,biology.protein ,Immunology and Allergy ,Animals ,Humans ,Cell Lineage ,Tyrosine kinase ,CD8 ,Signal Transduction - Abstract
Summary: Recent experiments in our laboratory have focused on the receptor engagements required for the differentiation of fully mature, single positive thymocytes from their double positive precursors. We have used a novel approach which involves the ligation of surface receptors on immature thymocytes with genetically engineered F(ab′)2 reagents, which, unlike conventional antibodies, do not aggregate the CD3 complex to such an extent as to induce extensive deletion of these cells. The experimental data presented in this review indicate that differentiation of the two mature CD4 and CD8 lineages occurs in response to distinct intracellular signals induced by particular receptor engagements. The data suggest that the tyrosine kinase p56kk (lck) plays a crucial role in determining lineage choice, in that maturation of thymocytes into the CD4 lineage occurs upon recruitment of active lck to the T-cell receptor (TCR)7CD3 complex, whereas CDS maturation can be induced by CD3 ligation in the absence of CO-receptor-mediated lck recruitment. A central role for lck activity in determining the threshold for differentiation of the CD4 lineage is revealed in experiments with thymi deficient for a regulator of lck activity, CD4-5. A model of thymocyte differentiation is presented in which we propose that the relative balance of signals delivered by TCR engagement and lck activation determines lineage choice.
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