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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.

An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension