title: An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension.
abstract: During vertebrate axis extension, adjacent tissue layers undergo profound morphological changes: within the neuroepithelium, neural tube closure and neural crest formation are occurring, while within the paraxial mesoderm somites are segmenting from the presomitic mesoderm (PSM). Little is known about the signals between these tissues that regulate their coordinated morphogenesis. Here, we analyze the posterior axis truncation of mouse Fgf3 null homozygotes and demonstrate that the earliest role of PSM-derived FGF3 is to regulate BMP signals in the adjacent neuroepithelium. FGF3 loss causes elevated BMP signals leading to increased neuroepithelium proliferation, delay in neural tube closure and premature neural crest specification. We demonstrate that elevated BMP4 depletes PSM progenitors in vitro, phenocopying the Fgf3 mutant, suggesting that excessive BMP signals cause the Fgf3 axis defect. To test this in vivo we increased BMP signaling in Fgf3 mutants by removing one copy of Noggin, which encodes a BMP antagonist. In such mutants, all parameters of the Fgf3 phenotype were exacerbated: neural tube closure delay, premature neural crest specification, and premature axis termination. Conversely, genetically decreasing BMP signaling in Fgf3 mutants, via loss of BMP receptor activity, alleviates morphological defects. Aberrant apoptosis is observed in the Fgf3 mutant tailbud. However, we demonstrate that cell death does not cause the Fgf3 phenotype: blocking apoptosis via deletion of pro-apoptotic genes surprisingly increases all Fgf3 defects including causing spina bifida. We demonstrate that this counterintuitive consequence of blocking apoptosis is caused by the increased survival of BMP-producing cells in the neuroepithelium. Thus, we show that FGF3 in the caudal vertebrate embryo regulates BMP signaling in the neuroepithelium, which in turn regulates neural tube closure, neural crest specification and axis termination. Uncovering this FGF3-BMP signaling axis is a major advance toward understanding how these tissue layers interact during axis extension with important implications in human disease.
authors.affiliation: Genetics of Vertebrate Development Section, Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Anderson
authors.affiliation: Instituto de Biología y Genética Molecular, Universidad de Valladolid y Consejo Superior de Investigaciones Científicas, Valladolid, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schimmang
authors.affiliation: Genetics of Vertebrate Development Section, Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D051518:Fibroblast Growth Factor 3 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008648:Mesoderm / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D009432:Neural Crest / Q000254:growth & development / Q000378:metabolism*; D054259:Neural Tube / Q000254:growth & development / Q000378:metabolism; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D019170:Somites / Q000254:growth & development / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D051518:Fibroblast Growth Factor 3; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C489197:Fgf3 protein, mouse