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

PLoS Genet. 2016 May 4;12(5):e1006018. doi: 10.1371/journal.pgen.1006018. eCollection 2016 May.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Bone Morphogenetic Protein 4 / genetics*
  • Bone Morphogenetic Protein 4 / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Death / genetics
  • Fibroblast Growth Factor 3 / genetics*
  • Fibroblast Growth Factor 3 / metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Mesoderm / growth & development
  • Mesoderm / metabolism
  • Mice
  • Neural Crest / growth & development
  • Neural Crest / metabolism*
  • Neural Tube / growth & development
  • Neural Tube / metabolism
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / metabolism
  • Neural Tube Defects / pathology
  • Signal Transduction / genetics
  • Somites / growth & development
  • Somites / metabolism

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Carrier Proteins
  • Fgf3 protein, mouse
  • Fibroblast Growth Factor 3
  • noggin protein

Grants and funding

This work was supported by the Center for Cancer Research of the Intramural Research Program of the National Institutes of Health through the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.