19 results on '"Domsch, Katrin"'
Search Results
2. Hox function and specificity – A tissue centric view
- Author
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Pinto, Pedro B., Domsch, Katrin, and Lohmann, Ingrid
- Published
- 2024
- Full Text
- View/download PDF
3. Specificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities
- Author
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Pinto, Pedro B., Domsch, Katrin, Gao, Xuefan, Wölk, Michaela, Carnesecchi, Julie, and Lohmann, Ingrid
- Published
- 2022
- Full Text
- View/download PDF
4. Hox dosage contributes to flight appendage morphology in Drosophila
- Author
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Paul, Rachel, Giraud, Guillaume, Domsch, Katrin, Duffraisse, Marilyne, Marmigère, Frédéric, Khan, Soumen, Vanderperre, Solene, Lohmann, Ingrid, Stoks, Robby, Shashidhara, L. S., and Merabet, Samir
- Published
- 2021
- Full Text
- View/download PDF
5. Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity
- Author
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Carnesecchi, Julie, Sigismondo, Gianluca, Domsch, Katrin, Baader, Clara Eva Paula, Rafiee, Mahmoud-Reza, Krijgsveld, Jeroen, and Lohmann, Ingrid
- Published
- 2020
- Full Text
- View/download PDF
6. Single‐cell RNA sequencing of motoneurons identifies regulators of synaptic wiring in Drosophila embryos.
- Author
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Velten, Jessica, Gao, Xuefan, Van Nierop y Sanchez, Patrick, Domsch, Katrin, Agarwal, Rashi, Bognar, Lena, Paulsen, Malte, Velten, Lars, and Lohmann, Ingrid
- Abstract
The correct wiring of neuronal circuits is one of the most complex processes in development, since axons form highly specific connections out of a vast number of possibilities. Circuit structure is genetically determined in vertebrates and invertebrates, but the mechanisms guiding each axon to precisely innervate a unique pre‐specified target cell are poorly understood. We investigated Drosophila embryonic motoneurons using single‐cell genomics, imaging, and genetics. We show that a cell‐specific combination of homeodomain transcription factors and downstream immunoglobulin domain proteins is expressed in individual cells and plays an important role in determining cell‐specific connections between differentiated motoneurons and target muscles. We provide genetic evidence for a functional role of five homeodomain transcription factors and four immunoglobulins in the neuromuscular wiring. Knockdown and ectopic expression of these homeodomain transcription factors induces cell‐specific synaptic wiring defects that are partly phenocopied by genetic modulations of their immunoglobulin targets. Taken together, our data suggest that homeodomain transcription factor and immunoglobulin molecule expression could be directly linked and function as a crucial determinant of neuronal circuit structure. Synopsis: Single‐cell RNA‐seq of Drosophila embryonic motoneurons combined with imaging and genetic perturbation suggests a linked homeodomain transcription factor – immunoglobulin program critical for synaptic wiring in the neuromuscular system. Single‐cell transcriptomes of Drosophila embryonic motoneurons were mapped along the AP axis using Hox gene expression as spatial markers.Homeodomain transcription factor (TF) and Immunoglobulin (Ig) genes were found to be highly variably expressed within twitlow motoneurons.Functional analysis suggested a regulatory and functional link between homeodomain TFs and Ig domain proteins in synaptic wiring.Common signatures of homeodomain TF expression were found in matching synaptic partners in the neuromuscular system. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II.
- Author
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Carnesecchi, Julie, Boumpas, Panagiotis, van Nierop y Sanchez, Patrick, Domsch, Katrin, Pinto, Hugo Daniel, Borges Pinto, Pedro, and Lohmann, Ingrid
- Published
- 2022
- Full Text
- View/download PDF
8. Maternal inheritance of twist and analysis of MAPK activation in embryos of the polychaete annelid Platynereis dumerilii
- Author
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Pfeifer, Kathrin, Schaub, Christoph, Domsch, Katrin, Dorresteijn, Adriaan, Wolfstetter, Georg, and Institut für Allgemeine und Spezielle Zoologie
- Subjects
Cell biology ,Cell signaling ,Embryology ,MAPK signaling cascades ,Embryo, Nonmammalian ,animal structures ,Gene Identification and Analysis ,Developmental Signaling ,Gene Expression ,lcsh:Medicine ,Signal transduction ,Cell Fate Determination ,Zoological sciences ,Molecular Genetics ,ddc:590 ,Molecular Cell Biology ,Morphogenesis ,Genetics ,Animals ,RNA, Messenger ,lcsh:Science ,Biology and life sciences ,Twist-Related Protein 1 ,lcsh:R ,Signaling cascades ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Polychaeta ,Molecular Development ,Enzyme Activation ,Female ,lcsh:Q ,Mitogen-Activated Protein Kinases ,Organism Development ,Research Article ,Developmental Biology - Abstract
In this study, we aimed to identify molecular mechanisms involved in the specification of the 4d (mesentoblast) lineage in Platynereis dumerilii. We employ RT-PCR and in situ hybridization against the Platynereis dumerilii twist homolog (Pdu-twist) to reveal mesodermal specification within this lineage. We show that Pdu-twist mRNA is already maternally distributed. After fertilization, ooplasmatic segregation leads to relocation of Pdu-twist transcripts into the somatoblast (2d) lineage and 4d, indicating that the maternal component of Pdu-twist might be an important prerequisite for further mesoderm specification but does not represent a defining characteristic of the mesentoblast. However, after the primordial germ cells have separated from the 4d lineage, zygotic transcription of Pdu-twist is exclusively observed in the myogenic progenitors, suggesting that mesodermal specification occurs after the 4d stage. Previous studies on spiral cleaving embryos revealed a spatio-temporal correlation between the 4d lineage and the activity of an embryonic organizer that is capable to induce the developmental fates of certain micromeres. This has raised the question if specification of the 4d lineage could be connected to the organizer activity. Therefore, we aimed to reveal the existence of such a proposed conserved organizer in Platynereis employing antibody staining against dpERK. In contrast to former observations in other spiralian embryos, activation of MAPK signaling during 2d and 4d formation cannot be detected which questions the existence of a conserved connection between organizer function and specification of the 4d lineage. However, our experiments unveil robust MAPK activation in the prospective nephroblasts as well as in the macromeres and some micromeres at the blastopore in gastrulating embryos. Inhibition of MAPK activation leads to larvae with a shortened body axis, defects in trunk muscle spreading and improper nervous system condensation, indicating a critical function for MAPK signaling for the reorganization of embryonic tissues during the gastrulation process.
- Published
- 2014
9. Funktionelle Analysen von abba und mib2, zweier Gene, die zum Erhalt der Integrität von Muskel- und Sarkomerstrukturen in Drosophila melanogaster benötigt werden
- Author
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Domsch, Katrin
- Subjects
Muskel ,Muskelentwicklung ,Naturwissenschaftliche Fakultät -ohne weitere Spezifikation ,Sarkomer ,ddc:570 ,Taufliege - Abstract
The precise organization of the sarcomeric pattern is evolutionarily conserved and critical for muscle function. Currently, the mechanisms underlying the stabilization of the whole muscle and the sarcomeric architecture are not fully understood. My thesis is focusing on elucidating the mechanisms of sarcomere stabilisation and is composed of two parts. In the first part, I investigated the functional importance of different domains in the Drosophila Mib2 protein. In the second part, I analysed the function of a new Drosophila muscle protein Abba (Another B-Box affiliate). (1) Published data identified Mib2 as an important protein for the maintenance of the integrity of larval muscles. The loss of Mib2 results in detached muscles as the consequence of apoptosis within the fully established larval musculature during embryogenesis. Previous genetic experiments also showed that mib2 function in stabilising the muscles does not require the RING fingers and by extrapolating its ubiquitin ligase activity. In my genetic analysis, I tested numerous constructs, which lack single or a combination of protein domains for their ability to rescue the abba mutant phenotype. I demonstrated that the ANK repeats, which likely constitute a protein-protein interaction domain, and the conserved MIB domains are critical for mib2 function, strongly suggesting that Mib2 functions as an adapter-type of protein in maintaining the integrity of the larval muscle. (2) Abba, a member of the TRIM/RBCC protein superfamily, was original identified as a Mib2 interacting protein. Based upon my thesis work, I can conclude that abba plays an essential role in maintaining the sarcomere structure. abba mutant larvae show thinner and shorter myofibers with disrupted muscle filaments, as well as compromised muscle function. The mutants die during early pupal stages, displaying morphogenetic defects during metamorphosis. Additional genetic analysis, showed that abba functionally interacts with mlp84B, sls/kettin and α-actinin, which encode for Z-disc associated proteins. Using RNAi technology, I was also able to analyse abba function during the adult stages. Flies with abba RNAi show aberrant myofibrils with unstable Z-discs and missing M-lines. Further studies indicate that presumed protein-protein interaction domains and RING fingers are functionally important, suggesting that Abba acts as a ubiquitin ligase and an adapter type of protein. Altogether, my data indicate that Abba has a pivotal role for ensuring the integrity of Z-discs and M-lines during muscle formation and remodeling phases in Drosophila. Die strukturelle Stabilisierung der kleinesten funktionellen Einheit innerhalb der Muskulatur, des Sarkomers, ist entscheidend für die Funktionsfähigkeit der Muskeln. Die Stabilisierungsprozesse, beziehungsweise die ihnen zugrundeliegenden Mechanismen, sind aber noch nicht ausreichend erforscht. Um diese Mechanismen näher zu charakterisieren habe ich mich in meiner Arbeit mit zwei Themen befasst: erstens, mit der funktionellen Analyse der einzelnen Proteindomänen von Mib2 und zweitens, der Charakterisierung des neuen muskelspezifischen Gens abba (another B-Box affiliate) in Drosophila melanogaster. (1) In der Literatur ist Mib2 als essentieller Faktor, der für den Erhalt der larvalen Muskulatur entscheidend ist, beschrieben. In mib2 Mutanten lösen sich die Muskeln aufgrund von Apoptose von ihren Anheftungsstellen und runden sich in den späten embryonalen Stadien ab. Genetische Analysen haben gezeigt, dass die Funktion von Mib2 beim Erhalt der Muskelstrukturen nicht von den funktionellen Eigenschaften der RING-Finger Domänen abhängt. Durch zusätzliche genetische Rettungsanalysen mit zahlreichen Proteindomänen Deletionskonstrukten, welche jeweils eine oder mehrere Domänen eliminieren, konnte ich aber zeigen, dass sowohl die konservierte MIB Domäne als auch die ANK repeats funktionell wichtig für die Funktionsweise von Mib2 sind. Beide Domänen fungieren als Protein-Protein Interaktionsdomänen und weisen auf eine mögliche Funktion als Adapter-Protein hin. (2) Abba gehört zur TRIM/RBCC Superfamilie und wurde als potentieller Interaktionspartner von Mib2 entdeckt. In Verlauf dieser Arbeit habe ich mit Hilfe eines „imprecise excision screen” zahlreiche spezifische mutante abba Allele identifiziert. In Larven, die homozygot für diese abba Allele sind, sind dünnere und schmalere Muskeln mit zerstörter Muskelfilamentanordnung erkennbar. Die mutanten Allele sind pupal lethal und zeigen morphologische Defekte während der Metamorphose. Durch weitere genetische Analysen konnte ich zeigen, dass abba funktionell mit Genen, die für Z-Scheiben Proteine codieren, wie mlp84B, sls/kettin und α-actinin, interagiert. Mit Hilfe der RNAi Technik ist es mir gelungen den Verlust von abba auch in den adulten Stadien phänotypisch zu untersuchen. Die Reduktion von abba resultiert hierbei in schmalen und dünnen Myofibrillen mit instabilen Z-Scheiben und dem Verlust von M-Linien. Des Weiteren konnte ich zeigen, dass alle Proteindomänen von Abba eine funktionelle Relevanz aufweisen, es wahrscheinlich Ubiquitin-Ligase Aktivität besitzt und/oder als Adapter-Protein fungiert. Zusammengefasst zeigen meine Analysen, dass Abba einen essentiellen Faktor bei den Prozessen der Sarkomerstabilisierung in der larvalen und adulten Muskulatur von Drosophila repräsentiert.
- Published
- 2013
10. Identification of the essential protein domains for Mib2 function during the development of the Drosophila larval musculature and adult flight muscles.
- Author
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Domsch, Katrin, Acs, Andreas, Obermeier, Claudia, Nguyen, Hanh T., and Reim, Ingolf
- Subjects
- *
DROSOPHILA development , *PROTEIN domains , *INSECT larvae , *UBIQUITIN ligases , *PROTEOMICS - Abstract
The proper differentiation and maintenance of myofibers is fundamental to a functional musculature. Disruption of numerous mostly structural factors leads to perturbations of these processes. Among the limited number of known regulatory factors for these processes is Mind bomb2 (Mib2), a muscle-associated E3 ubiquitin ligase, which was previously established to be required for maintaining the integrity of larval muscles. In this study, we have examined the mechanistic aspects of Mib2 function by performing a detailed functional dissection of the Mib2 protein. We show that the ankyrin repeats, in its entirety, and the hitherto uncharacterized Mib-specific domains (MIB), are important for the major function of Mib2 in skeletal and visceral muscles in the Drosophila embryo. Furthermore, we characterize novel mib2 alleles that have arisen from a forward genetic screen aimed at identifying regulators of myogenesis. Two of these alleles are viable, but flightless hypomorphic mib2 mutants, and harbor missense mutations in the MIB domain and RING finger, respectively. Functional analysis of these new alleles, including in vivo imaging, demonstrates that Mib2 plays an additional important role in the development of adult thorax muscles, particularly in maintaining the larval templates for the dorsal longitudinal indirect flight muscles during metamorphosis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
11. Maternal Inheritance of Twist and Analysis of MAPK Activation in Embryos of the Polychaete Annelid Platynereis dumerilii.
- Author
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Pfeifer, Kathrin, Schaub, Christoph, Domsch, Katrin, Dorresteijn, Adriaan, and Wolfstetter, Georg
- Subjects
EMBRYOS ,PLATYNEREIS dumerilii ,MITOGEN-activated protein kinases ,GERM cells ,PROGENITOR cells ,DEVELOPMENTAL biology - Abstract
In this study, we aimed to identify molecular mechanisms involved in the specification of the 4d (mesentoblast) lineage in Platynereis dumerilii. We employ RT-PCR and in situ hybridization against the Platynereis dumerilii twist homolog (Pdu-twist) to reveal mesodermal specification within this lineage. We show that Pdu-twist mRNA is already maternally distributed. After fertilization, ooplasmatic segregation leads to relocation of Pdu-twist transcripts into the somatoblast (2d) lineage and 4d, indicating that the maternal component of Pdu-twist might be an important prerequisite for further mesoderm specification but does not represent a defining characteristic of the mesentoblast. However, after the primordial germ cells have separated from the 4d lineage, zygotic transcription of Pdu-twist is exclusively observed in the myogenic progenitors, suggesting that mesodermal specification occurs after the 4d stage. Previous studies on spiral cleaving embryos revealed a spatio-temporal correlation between the 4d lineage and the activity of an embryonic organizer that is capable to induce the developmental fates of certain micromeres. This has raised the question if specification of the 4d lineage could be connected to the organizer activity. Therefore, we aimed to reveal the existence of such a proposed conserved organizer in Platynereis employing antibody staining against dpERK. In contrast to former observations in other spiralian embryos, activation of MAPK signaling during 2d and 4d formation cannot be detected which questions the existence of a conserved connection between organizer function and specification of the 4d lineage. However, our experiments unveil robust MAPK activation in the prospective nephroblasts as well as in the macromeres and some micromeres at the blastopore in gastrulating embryos. Inhibition of MAPK activation leads to larvae with a shortened body axis, defects in trunk muscle spreading and improper nervous system condensation, indicating a critical function for MAPK signaling for the reorganization of embryonic tissues during the gastrulation process. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
12. Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles.
- Author
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Rose, Marcel, Domsch, Katrin, Bartle-Schultheis, Jakob, Reim, Ingolf, and Schaub, Christoph
- Abstract
Genesis of syncytial muscles is typically considered as a paradigm for an irreversible developmental process. Notably, transdifferentiation of syncytial muscles is naturally occurring during Drosophila development. The ventral longitudinal heart-associated musculature (VLM) arises by a unique mechanism that revokes differentiation states of so-called alary muscles and comprises at least two distinct steps: syncytial muscle cell fragmentation into single myoblasts and successive reprogramming into founder cells that orchestrate de novo fiber formation of the VLM lineage. Here, we provide evidence that the mesodermal master regulator twist plays a key role during this reprogramming process. Acting downstream of Drosophila Tbx1 (Org-1), Twist is regulating the activity of the Hippo pathway effector Yorkie and is required for the initiation of syncytial muscle dedifferentiation and fragmentation. Subsequently, fibroblast growth factor receptor (FGFR)-Ras-mitogen-activated protein kinase (MAPK) signaling in resulting mononucleated myoblasts maintains Twist expression, thereby stabilizing nuclear Yorkie activity and inducing their lineage switch into founder cells of the VLM. [Display omitted] • Twist mediates fate plasticity during transdifferentiation of syncytial muscle cells • Twist induces Yorkie activity to promote dedifferentiation and reprogramming • Twist/Yki/FGFR regulatory axis is required for lineage switch during reprogramming Rose et al. investigate the molecular mechanisms that mediate cellular plasticity in syncytial muscles. Using a naturally occurring transdifferentiation mechanism as a model, they identify Twist as a master regulator that controls muscle lineage fate plasticity via altering of syncytial differentiation states and that facilitates lineage reprogramming of myoblasts. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
13. Abba is an essential TRIM/RBCC protein to maintain the integrity of sarcomeric cytoarchitecture.
- Author
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Domsch, Katrin, Ezzeddine, Nader, and Nguyen, Hanh T.
- Subjects
- *
CYTOARCHITECTONICS , *SKELETAL muscle , *TRIM proteins , *F-actin , *MYOSIN , *RNA interference - Abstract
Organized sarcomeric striations are an evolutionarily conserved hallmark of functional skeletal muscles. Here, we demonstrate that the Drosophila Abba protein, a member of the TRIM/RBCC superfamily, has a pivotal regulatory role in maintaining proper sarcomeric cytoarchitecture during development and muscle usage. abba mutant embryos initially form muscles, but F-actin and Myosin striations become progressively disrupted when the muscles undergo growth and endure increased contractile forces during larval development. Abnormal Myosin aggregates and myofiber atrophy are also notable in the abba mutants. The larval defects result in compromised muscle function, and hence important morphogenetic events do not occur properly during pupation, leading to lethality. Abba is localized at larval Z-discs, and genetic evidence indicates that abba interacts with α-actinin, kettin/D-titin and mlp84B, genes that encode important Z-disc proteins for stable myofibrillar organization and optimal muscle function. RNAi experiments and ultrastructural analysis reveal that Abba has an additional crucial role in sarcomere maintenance in adult muscles. Abba is required to ensure the integrity and function of Z-discs and M-lines. Rescue experiments further show that Abba function is dependent upon its B-box/coiledcoil domain, NHL repeats and RING finger domain. The importance of these presumed protein-protein interactions and ubiquitin ligaseassociated domains supports our hypothesis that Abba is needed for specific protein complex formation and stabilization at Z-discs and M-lines. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
14. An Evolutionary Perspective on Hox Binding Site Preferences in Two Different Tissues.
- Author
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Folkendt, Laura, Lohmann, Ingrid, and Domsch, Katrin
- Subjects
BINDING sites ,EPIBLAST ,REGULATOR genes ,TRANSCRIPTION factors ,CELL physiology ,HISTONES - Abstract
Transcription factor (TF) networks define the precise development of multicellular organisms. While many studies focused on TFs expressed in specific cell types to elucidate their contribution to cell specification and differentiation, it is less understood how broadly expressed TFs perform their precise functions in the different cellular contexts. To uncover differences that could explain tissue-specific functions of such TFs, we analyzed here genomic chromatin interactions of the broadly expressed Drosophila Hox TF Ultrabithorax (Ubx) in the mesodermal and neuronal tissues using bioinformatics. Our investigations showed that Ubx preferentially interacts with multiple yet tissue-specific chromatin sites in putative regulatory regions of genes in both tissues. Importantly, we found the classical Hox/Ubx DNA binding motif to be enriched only among the neuronal Ubx chromatin interactions, whereas a novel Ubx-like motif with rather low predicted Hox affinities was identified among the regions bound by Ubx in the mesoderm. Finally, our analysis revealed that tissues-specific Ubx chromatin sites are also different with regards to the distribution of active and repressive histone marks. Based on our data, we propose that the tissue-related differences in Ubx binding behavior could be a result of the emergence of the mesoderm as a new germ layer in triploblastic animals, which might have required the Hox TFs to relax their binding specificity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
15. Maternal Inheritance of Twist and Analysis of MAPK Activation in Embryos of the Polychaete Annelid Platynereis dumerilii.
- Author
-
Pfeifer, Kathrin, Schaub, Christoph, Domsch, Katrin, Dorresteijn, Adriaan, and Wolfstetter, Georg
- Subjects
- *
EMBRYOS , *PLATYNEREIS dumerilii , *MITOGEN-activated protein kinases , *GERM cells , *PROGENITOR cells , *DEVELOPMENTAL biology - Abstract
In this study, we aimed to identify molecular mechanisms involved in the specification of the 4d (mesentoblast) lineage in Platynereis dumerilii. We employ RT-PCR and in situ hybridization against the Platynereis dumerilii twist homolog (Pdu-twist) to reveal mesodermal specification within this lineage. We show that Pdu-twist mRNA is already maternally distributed. After fertilization, ooplasmatic segregation leads to relocation of Pdu-twist transcripts into the somatoblast (2d) lineage and 4d, indicating that the maternal component of Pdu-twist might be an important prerequisite for further mesoderm specification but does not represent a defining characteristic of the mesentoblast. However, after the primordial germ cells have separated from the 4d lineage, zygotic transcription of Pdu-twist is exclusively observed in the myogenic progenitors, suggesting that mesodermal specification occurs after the 4d stage. Previous studies on spiral cleaving embryos revealed a spatio-temporal correlation between the 4d lineage and the activity of an embryonic organizer that is capable to induce the developmental fates of certain micromeres. This has raised the question if specification of the 4d lineage could be connected to the organizer activity. Therefore, we aimed to reveal the existence of such a proposed conserved organizer in Platynereis employing antibody staining against dpERK. In contrast to former observations in other spiralian embryos, activation of MAPK signaling during 2d and 4d formation cannot be detected which questions the existence of a conserved connection between organizer function and specification of the 4d lineage. However, our experiments unveil robust MAPK activation in the prospective nephroblasts as well as in the macromeres and some micromeres at the blastopore in gastrulating embryos. Inhibition of MAPK activation leads to larvae with a shortened body axis, defects in trunk muscle spreading and improper nervous system condensation, indicating a critical function for MAPK signaling for the reorganization of embryonic tissues during the gastrulation process. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
16. The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II.
- Author
-
Carnesecchi J, Boumpas P, van Nierop Y Sanchez P, Domsch K, Pinto HD, Borges Pinto P, and Lohmann I
- Subjects
- Amino Acids, Animals, Binding Sites, Chromatin Immunoprecipitation Sequencing, Drosophila Proteins genetics, Drosophila melanogaster, Gene Expression Regulation, Models, Biological, Organ Specificity genetics, Protein Binding, Protein Interaction Domains and Motifs, RNA, Messenger genetics, RNA, Messenger metabolism, RNA-Binding Proteins metabolism, RNA-Seq, Drosophila Proteins metabolism, Homeodomain Proteins metabolism, RNA genetics, RNA metabolism, RNA Polymerase II metabolism, RNA Splicing, Transcription Factors metabolism
- Abstract
Transcription factors (TFs) play a pivotal role in cell fate decision by coordinating gene expression programs. Although most TFs act at the DNA layer, few TFs bind RNA and modulate splicing. Yet, the mechanistic cues underlying TFs activity in splicing remain elusive. Focusing on the Drosophila Hox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm and Drosophila cells indicate that Ubx regulates mRNA expression and splicing to promote distinct outcomes in defined cellular contexts. Our results demonstrate a new RNA-binding ability of Ubx. We find that the N51 amino acid of the DNA-binding Homeodomain is non-essential for RNA interaction in vitro, but is required for RNA interaction in vivo and Ubx splicing activity. Moreover, mutation of the N51 amino acid weakens the interaction between Ubx and active RNA Polymerase II (Pol II). Our results reveal that Ubx regulates elongation-coupled splicing, which could be coordinated by a dynamic interplay with active Pol II on chromatin. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
- Full Text
- View/download PDF
17. The Hox Transcription Factor Ubx Ensures Somatic Myogenesis by Suppressing the Mesodermal Master Regulator Twist.
- Author
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Domsch K, Schröder J, Janeschik M, Schaub C, and Lohmann I
- Subjects
- Animals, Drosophila Proteins genetics, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Gene Expression Regulation, Developmental, Homeodomain Proteins genetics, Polycomb-Group Proteins metabolism, Promoter Regions, Genetic, Transcription Factors genetics, Twist-Related Protein 1 genetics, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Homeodomain Proteins metabolism, Mesoderm metabolism, Muscle Development, Transcription Factors metabolism, Twist-Related Protein 1 metabolism
- Abstract
Early lineage-specific master regulators are essential for the specification of cell types. However, once cells are committed to a specific fate, it is critical to restrict the activity of such factors to enable differentiation. To date, it remains unclear how these factors are silenced. Using the Drosophila mesoderm as a model and a comparative genomic approach, we identify the Hox transcription factor Ultrabithorax (Ubx) to be critical for the repression of the master regulator Twist. Mesoderm-specific Ubx loss-of-function experiments using CRISPR-Cas9 and overexpression studies demonstrate that Ubx majorly impacts twist transcription. A mechanistic analysis reveals that Ubx requires the NK-homeodomain protein Tinman to bind to the twist promoter. Furthermore, we find these factor interactions to be critical for silencing by recruiting the Polycomb DNA binding protein Pleiohomeotic. Altogether, our data reveal that Ubx is a critical player in mediating the silencing of Twist, which is crucial for coordinated muscle differentiation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
18. The Hox transcription factor Ubx stabilizes lineage commitment by suppressing cellular plasticity in Drosophila .
- Author
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Domsch K, Carnesecchi J, Disela V, Friedrich J, Trost N, Ermakova O, Polychronidou M, and Lohmann I
- Subjects
- Animals, Drosophila Proteins deficiency, Gene Knockdown Techniques, Polycomb-Group Proteins metabolism, Transcription Factors deficiency, Cell Plasticity, Drosophila physiology, Drosophila Proteins metabolism, Gene Expression Regulation, Developmental, Homeodomain Proteins metabolism, Transcription Factors metabolism
- Abstract
During development cells become restricted in their differentiation potential by repressing alternative cell fates, and the Polycomb complex plays a crucial role in this process. However, how alternative fate genes are lineage-specifically silenced is unclear. We studied Ultrabithorax (Ubx), a multi-lineage transcription factor of the Hox class, in two tissue lineages using sorted nuclei and interfered with Ubx in mesodermal cells. We find that depletion of Ubx leads to the de-repression of genes normally expressed in other lineages. Ubx silences expression of alternative fate genes by retaining the Polycomb Group protein Pleiohomeotic at Ubx targeted genomic regions, thereby stabilizing repressive chromatin marks in a lineage-dependent manner. Our study demonstrates that Ubx stabilizes lineage choice by suppressing the multipotency encoded in the genome via its interaction with Pho. This mechanism may explain why the Hox code is maintained throughout the lifecycle, since it could set a block to transdifferentiation in adult cells., Competing Interests: KD, JC, VD, JF, NT, OE, MP, IL No competing interests declared, (© 2019, Domsch et al.)
- Published
- 2019
- Full Text
- View/download PDF
19. The HOX-Apoptosis Regulatory Interplay in Development and Disease.
- Author
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Domsch K, Papagiannouli F, and Lohmann I
- Subjects
- Animals, Gene Expression Regulation, Developmental, Gene Expression Regulation, Leukemic, Gene Expression Regulation, Neoplastic, Homeodomain Proteins genetics, Humans, Leukemia genetics, Leukemia pathology, Neoplasms pathology, Transcription Factors genetics, Transcription Factors metabolism, Apoptosis physiology, Gene Expression Regulation, Genes, Homeobox, Homeodomain Proteins metabolism, Neoplasms genetics
- Abstract
Apoptosis is a cellular suicide program, which is on the one hand used to remove superfluous cells thereby promoting tissue or organ morphogenesis. On the other hand, the programmed killing of cells is also critical when potentially harmful cells emerge in a developing or adult organism thereby endangering survival. Due to its critical role apoptosis is tightly controlled, however so far, its regulation on the transcriptional level is less studied and understood. Hox genes, a highly conserved gene family encoding homeodomain transcription factors, have crucial roles in development. One of their prominent functions is to shape animal body plans by eliciting different developmental programs along the anterior-posterior axis. To this end, Hox proteins transcriptionally regulate numerous processes in a coordinated manner, including cell-type specification, differentiation, motility, proliferation as well as apoptosis. In this review, we will focus on how Hox proteins control organismal morphology and function by regulating the apoptotic machinery. We will first focus on well-established paradigms of Hox-apoptosis interactions and summarize how Hox transcription factors control morphological outputs and differentially shape tissues along the anterior-posterior axis by fine-tuning apoptosis in a healthy organism. We will then discuss the consequences when this interaction is disturbed and will conclude with some ideas and concepts emerging from these studies., (© 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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