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Tumor heterogeneity, the presence of multiple distinct subpopulations of cancer cells between patients or among the same tumors, poses a major challenge to current targeted therapies. The way these different subpopulations interact among themselves and the stromal niche environment, and how such interactions affect cancer stem cell behavior has remained largely unknown. Here, it is shown that an FGF‐BMP7‐INHBA signaling positive feedback loop integrates interactions among different cell populations, including mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration but also, with certain modifications, in cancer progression. The reciprocal dependence of basal stem cells and luminal epithelium is based on basal‐derived BMP7 and luminal‐derived INHBA, which promote their respective expansion, and is regulated by stromal‐epithelial FGF signaling. Targeting this interaction loop, for example, by reducing the function of one or more of its components, inhibits organ regeneration and breast cancer progression. The results have profound implications for overcoming drug resistance because of tumor heterogeneity in future targeted therapies. [ABSTRACT FROM AUTHOR]

Amphibians have a very high capacity for regeneration among tetrapods. This superior regeneration capability in amphibians can be observed in limbs, the tail, teeth, external gills, the heart, and some internal organs. The mechanisms underlying the superior organ regeneration capability have been studied for a long time. Limb regeneration has been investigated as the representative phenomenon for organ‐level regeneration. In limb regeneration, a prominent difference between regenerative and nonregenerative animals after limb amputation is blastema formation. A regeneration blastema requires the presence of nerves in the stump region. Thus, nerve regulation is responsible for blastema induction, and it has received much attention. Nerve regulation in regeneration has been investigated using the limb regeneration model and newly established alternative experimental model called the accessory limb model. Previous studies have identified some candidate genes that act as neural factors in limb regeneration, and these studies also clarified related events in early limb regeneration. Consistent with the nervous regulation and related events in limb regeneration, similar regeneration mechanisms in other organs have been discovered. This review especially focuses on the role of nerve‐mediated fibroblast growth factor in the initiation phase of organ regeneration. Comparison of the initiation mechanisms for regeneration in various amphibian organs allows speculation about a fundamental regenerative process. Research Highlights: Urodeles have a remarkable organ‐level regeneration ability.Nerve‐secreted Fgfs are the key molecules to initiate organ‐level regeneration.Fibroblast growth factor (FGF)‐signaling is important for the initiation of regeneration in multiple organs and species. [ABSTRACT FROM AUTHOR]

Craniofacial development involves several complex tissue movements including several fusion processes to form the frontonasal and maxillary structures, including the upper lip and palate. Each of these movements are controlled by many different factors that are tightly regulated by several integral morphogenetic signaling pathways. Subject to both genetic and environmental influences, interruption at nearly any stage can disrupt lip, nasal, or palate fusion and result in a cleft. Here, we discuss many of the genetic risk factors that may contribute to the presentation of orofacial clefts in patients, and several of the key signaling pathways and underlying cellular mechanisms that control lip and palate formation, as identified primarily through investigating equivalent processes in animal models, are examined. [ABSTRACT FROM AUTHOR]

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER‐phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER‐phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER‐phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3—master regulators of lysosomal biogenesis and autophagy—control ER‐phagy by inducing the expression of the ER‐phagy receptor FAM134B. The TFEB/TFE3‐FAM134B axis promotes ER‐phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK‐dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K‐PKB/Akt‐mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER‐phagy to respond to both metabolic and developmental cues. Synopsis: The signalling pathways inducing autophagic degradation of the endoplasmic reticulum (ER‐phagy) to regulate cellular homeostasis are ill‐defined. Here, ER‐phagy in chondrocytes promoting bone development is found to be regulated by fibroblast growth factor 18 (FGF18), which induces nuclear translocation of TFEB/TFE3 transcription factors and expression of FAM134B. MiTF/TFE transcription factors promote expression of FAM134B and ER‐phagy in mammalian cells.Prolonged starvation leads to the activation of the TFEB/TFE3‐FAM134B axis and ER‐phagy.In chondrocytes, FGF18 induces ER‐phagy through JNK‐mediated degradation of the IRS1 protein.FAM134B is required for protein secretion in chondrocytes, and for cartilage growth and bone mineralization in medaka fish. [ABSTRACT FROM AUTHOR]

Background: The basic ground plan of vertebrate hindbrain is established through a process of segmentation, which generates eight transient lineage‐restricted cellular compartments called rhombomeres (r). The segments adopt distinct individual identities in response to axial patterning signals. It is unclear whether signaling between rhombomeres plays a conserved role in regulating segmental patterning during hindbrain development. Results: Using tissue manipulations of rhombomeres in chicken embryos, we have uncovered roles for r2 and r4 in regulating the expression of EphA4 in r3 and r5. Perturbations of signaling pathways reveal that these regulatory inputs from r2 and r4 into EphA4 expression are mediated independent of inputs from Krox20 through cues involving fibroblast growth factor (FGF) signaling. These interactions are stage dependent and are set up in embryos with <10 somites. Conclusions: We show that r2 and r4 function as temporally dynamic signaling centers in the early patterning of adjacent hindbrain segments and this activity is dependent upon the FGF pathway. These results reveal that inter‐rhombomeric signaling is a conserved feature of the regulatory networks that control the specification of individual rhombomere identities in vertebrate hindbrain segmentation. However, the timing of when restricted domains of FGF signaling are coupled to formation of r4 may vary between the species. Key Findings: r2 and r4 function as temporally dynamic signaling centers in the hindbrain patterning.Signaling from r2 and r4 regulate EphA4 expression in r3 and r5.Inter‐rhombomeric cues from r2 and r4 are mediated by FGF signaling. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor 18 (FGF18) functions in the development of several tissues, including the lung, limb bud, palate, skeleton, central nervous system, and hair follicle. Mice containing a germline knockout of Fgf18 (Fgf18−/−) die shortly after birth. Postnatally, FGF18 is being evaluated for pathogenic roles in fibrosis and several types of cancer. The specific cell types that express FGF18 have been difficult to identify, and the function of FGF18 in postnatal development and tissue homeostasis has been hampered by the perinatal lethality of Fgf18 null mice. Results: We engineered a floxed allele of Fgf18 (Fgf18flox) that allows conditional gene inactivation and a CreERT2 knockin allele (Fgf18CreERT2) that allows the precise identification of cells that express Fgf18 and their lineage. We validated the Fgf18flox allele by targeting it in mesenchymal tissue and primary mesoderm during embryonic development, resulting in similar phenotypes to those observed in Fgf18 null mice. We also use the Fgf18CreERT2 allele, in combination with a conditional fluorescent reporter to confirm known and identify new sites of Fgf18 expression. Conclusion: These alleles will be useful to investigate FGF18 function during organogenesis and tissue homeostasis, and to target specific cell lineages at embryonic and postnatal time points. Key Findings: Successful generation of a floxed allele of Fgf18 and a tamoxifen inducible Cre recombinase allele driven by the Fgf18 promoter.Recapitulation of the Fgf18 null skeletal deformities by conditionally targeting Fgf18 in the mesenchyme.Identification of known and new sites of Fgf18 expression in the embryo, postnatal and juvenile skeleton, postnatal and adult visceral organs, and in the adult brain. [ABSTRACT FROM AUTHOR]

Background: The tissue‐specific transcriptional programs during normal development require tight control by distal cis‐regulatory elements, such as enhancers, with specific DNA sequences recognized by transcription factors, coactivators, and chromatin remodeling enzymes. Gata3 is a sequence‐specific DNA‐binding transcription factor that regulates formation of multiple tissues and organs, including inner ear, lens, mammary gland, T‐cells, urogenital system, and thyroid gland. In the eye, Gata3 has a highly restricted expression domain in the posterior part of the lens vesicle; however, the underlying regulatory mechanisms are unknown. Results: Here we describe the identification of a novel bipartite Gata3 lens‐specific enhancer located ∼18 kb upstream from its transcriptional start site. We also found that a 5‐kb Gata3 promoter possesses low activity in the lens. The bipartite enhancer contains arrays of AP‐1, Ets‐, and Smad1/5‐binding sites as well as binding sites for lens‐associated DNA‐binding factors. Transient transfection studies of the promoter with the bipartite enhancer showed enhanced activation by BMP4 and FGF2. Conclusions: These studies identify a novel distal enhancer of Gata3 with high activity in lens and indicate that BMP and FGF signaling can up‐regulate expression of Gata3 in differentiating lens fiber cells through the identified Gata3 enhancer and promoter elements. Developmental Dynamics 247:1186–1198, 2018. © 2018 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists Key Findings: Novel Gata3 lens‐specific enhancer is located 18 kb upstream of transcription start site.BMP and FGF signaling can regulate Gata3 expression during mouse lens development. [ABSTRACT FROM AUTHOR]

Signal transduction through multiple distinct pathways regulates and orchestrates the numerous biological processes comprising heart development. This review outlines the roles of the FGFR, EGFR, Wnt, BMP, Notch, Hedgehog, Slit/Robo, and other signaling pathways during four sequential phases of Drosophila cardiogenesis-mesoderm migration, cardiac mesoderm establishment, differentiation of the cardiac mesoderm into distinct cardiac cell types, and morphogenesis of the heart and its lumen based on the proper positioning and cell shape changes of these differentiated cardiac cells-and illustrates how these same cardiogenic roles are conserved in vertebrates. Mechanisms bringing about the regulation and combinatorial integration of these diverse signaling pathways in Drosophila are also described. This synopsis of our present state of knowledge of conserved signaling pathways in Drosophila cardiogenesis and the means by which it was acquired should facilitate our understanding of and investigations into related processes in vertebrates. Developmental Dynamics 246:641-656, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Homeobox genes play important roles in craniofacial morphogenesis. However, the characteristics of the transcription factor Hoxc during palate formation remain unclear. We examined the immunolocalization patterns of Hoxc5, Hoxc4, and Hoxc6 in palatogenesis of cleft palate ( Eh/ Eh) mice. On the other hand, mutations in the FGF/FGFR pathway are exclusively associated with syndromic forms of cleft palate. We also examined the immunolocalization of Fgfr1 and Erk1/2 to clarify their relationships with Hoxc in palatogenesis. Some palatal epithelial cells showed Hoxc5 labeling, while almost no labeling of mesenchymal cells was observed in +/+ mice. As palate formation progressed in +/+ mice, Hoxc5, Hoxc4, and Hoxc6 were observed in medial epithelial seam cells. Hoxc5 and Hoxc6 were detected in the oral epithelium. The palatal mesenchyme also showed intense staining for Fgfr1 and Erk1/2 with progression of palate formation. In contrast, the palatal shelves of Eh/ Eh mice exhibited impaired horizontal growth and failed to fuse, resulting in a cleft. Hoxc5 was observed in a few epithelial cells and diffusely in the mesenchyme of Eh/ Eh palatal shelves. No or little labeling of Fgfr1 and Erk1/2 was detected in the cleft palate of Eh/ Eh mice. These findings suggest that Hoxc genes are involved in palatogenesis. Furthermore, there may be the differences in the localization pattern between Hoxc5, Hoxc4, and Hoxc6. Additionally, Hoxc distribution in palatal cells during palate development may be correlated with FGF signaling. (228/250 words) © 2016 Japanese Teratology Society [ABSTRACT FROM AUTHOR]

Background: Induction of gene expression in a specific cell and a defined time window is desirable to investigate gene function at the cellular level during morphogenesis. To achieve this, we attempted to introduce the infrared laser-evoked gene operator system (IR-LEGO, Kamei et al., 2009) in the Drosophila embryo. In this technique, infrared laser light illumination induces genes to be expressed under the control of heat shock promoters at the single cell level. Results: We applied IR-LEGO to a transgenic fly stock, HS-eGFP, in which the enhanced green fluorescent protein (eGFP) gene is placed under the control of heat shock protein 70 promoter, and showed that eGFP expression can be induced in single cells within 1-2 hr after IR illumination. Furthermore, induction of HS-Branchless transgene encoding the Drosophila fibroblast growth factor (FGF) effectively altered the migration and branching patterns of the tracheal system. Conclusions: Our results indicated that IR-LEGO is a promising choice for the timely control of gene expression in a small group of cells in the Drosophila embryo. By using IR-LEGO, we further demonstrated that the tracheal terminal branching program is sensitive to localized expression of exogenous FGF. Developmental Dynamics 244:479-487, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: During the course of development, the vertebrate nephric duct (ND) extends and migrates from the place of its initial formation, adjacent to the anterior somites, until it inserts into the bladder or cloaca in the posterior region of the embryo. The molecular mechanisms that guide ND migration are poorly understood. Results: A novel Gata3-enhancer-Gfp-based chick embryo live imaging system was developed that permits documentation of ND migration at the individual cell level for the first time. FGF Receptors and FGF response genes are expressed in the ND, and FGF ligands are expressed in surrounding tissues. FGF receptor inhibition blocked nephric duct migration. Individual inhibitors of the Erk, p38, or Jnk pathways did not affect duct migration, but inhibition of all three pathways together did inhibit migration of the duct. A localized source of FGF8 placed adjacent to the nephric duct did not affect the duct migration path. Conclusions: FGF signaling acts as a 'motor' that is required for duct migration, but other signals are needed to determine the directionality of the duct migration pathway. Developmental Dynamics 244:157-167, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Gastrulation is the process in which the three germ layers are formed that contribute to the formation of all major tissues in the developing embryo. We here review mouse genetic models in which defective gastrulation leads to mesoderm insufficiencies in the embryo. Depending on severity of the abnormalities, the outcomes range from incompatible with embryonic survival to structural birth defects, such as heart defects, spina bifida, or caudal dysgenesis. The combined evidence from the mutant models supports the notion that these congenital anomalies can originate from perturbations of mesoderm specification, epithelial-mesenchymal transition, and mesodermal cell migration. Knowledge about the molecular pathways involved may help to improve strategies for the prevention of major structural birth defects. Birth Defects Research (Part A) 100:608-622, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND Mutations in Fibroblastic Growth Factor Receptors (FGFR) have been associated with human craniosynostotic birth defects like Crouzon syndrome. Several anecdotes and case reports have indicated higher incidence of gastrointestinal tract disorders in FGFR-associated craniosynostotic birth defects. Our objective was to characterize esophageal defects in a mouse model of human Crouzon syndrome, with a mutation in codon 290 of FGFR2. METHODS Dissected esophagi of Fgfr2W290R postnatal heterozygous (HET) and wild-type mice were analyzed by histological staining, immunohistochemically with cell proliferation marker, and functionally by strain gauge measures of electrically evoked contractile force. RESULTS The esophagi of HETs were noticeably smaller but with wider lumen than those of wild-type littermates. The HET esophagi showed a decrease in proliferation and an increase in expression of Sonic Hedgehog as compared to wild-type esophagi. Histological investigations revealed reduced amounts and disorganization of collagen in muscle layers. Functional analysis revealed altered contractile properties in HET with reduced peak amplitude and prolonged duration of evoked contractile force response and lower stimulation threshold. CONCLUSION The defects observed in the esophagus of the mutant may explain some of the clinical symptoms observed in humans, for example, recurrent vomiting, gastroesophageal reflux, and esophageal strictures. Taken together, our results provide evidence for the importance of Fibroblastic Growth Factor signaling in the growth and patterning of the esophagus, providing a possible scientific basis for the gastrointestinal tract clinical findings in craniosynostotic patients. Furthermore, the findings also provide a sound scientific rationale for any changes in the clinical management of gastrointestinal tract problems in patients with craniosynostotic defects. Birth Defects Research (Part A) 97:578-586, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In the ascidian embryo, a fibroblast growth factor (FGF)-like signal from presumptive endoderm blastomeres between the 32-cell and early 64-cell stages induces the formation of notochord and mesenchyme cells. However, it has not been known whether endogenous FGF signaling is involved in the process. Here it is shown that 64-cell embryos exhibit a marked increase in endogenous extracellular signal-regulated kinase (ERK/MAPK) activity. The increase in ERK activity was reduced by treatment with an FGF receptor 1 inhibitor, SU5402, and a MEK (ERK kinase/MAPKK) inhibitor, U0126. Both drugs blocked the formation of notochord and mesenchyme when embryos were treated at the 32-cell stage, but not at the 2- or 110-cell stages. The dominant-negative form of Ras also suppressed notochord and mesenchyme formation. Both inhibitors suppressed induction by exogenous basic FGF. These results suggest that the FGF signaling cascade is indeed necessary for the formation of notochord and mesenchyme cells during ascidian embryogenesis. It is also shown that FGF signaling is required for formation of the secondary notochord, secondary muscle and neural tissues, and at least ERK activity is necessary for the formation of trunk lateral cells and posterior endoderm. Therefore, FGF and MEK signaling are required for the formation of various tissues in the ascidian embryo. [ABSTRACT FROM AUTHOR]

High uncoupling protein 1 (Ucp1) expression is a characteristic of differentiated brown adipocytes and is linked to adipogenic differentiation. Paracrine fibroblast growth factor 8b (FGF8b) strongly induces Ucp1 transcription in white adipocytes independent of adipogenesis. Here, we report that FGF8b and other paracrine FGFs act on brown and white preadipocytes to upregulate Ucp1 expression via a FGFR1-MEK1/2-ERK1/2 axis, independent of adipogenesis. Transcriptomic analysis revealed an upregulation of prostaglandin biosynthesis and glycolysis upon Fgf8b treatment of preadipocytes. Oxylipin measurement by LC-MS/MS in FGF8b conditioned media identified prostaglandin E2 as a putative mediator of FGF8b induced Ucp1 transcription. RNA interference and pharmacological inhibition of the prostaglandin E2 biosynthetic pathway confirmed that PGE2 is causally involved in the control over Ucp1 transcription. Importantly, impairment of or failure to induce glycolytic flux blunted the induction of Ucp1, even in the presence of PGE2. Lastly, a screening of transcription factors identified Nrf1 and Hes1 as required regulators of FGF8b induced Ucp1 expression. Thus, we conclude that paracrine FGFs co-regulate prostaglandin and glucose metabolism to induce Ucp1 expression in a Nrf1/Hes1-dependent manner in preadipocytes, revealing a novel regulatory network in control of Ucp1 expression in a formerly unrecognized cell type. [ABSTRACT FROM AUTHOR]