Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis

PLoS Genet. 2017 Oct 13;13(10):e1007047. doi: 10.1371/journal.pgen.1007047. eCollection 2017 Oct.


The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the lacrimal gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes lacrimal gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for lacrimal gland development.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Fibroblast Growth Factor 10 / genetics*
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Humans
  • Lacrimal Apparatus / growth & development*
  • Lacrimal Apparatus / metabolism
  • Mesoderm / growth & development
  • Mice
  • Morphogenesis / genetics*
  • Neural Crest / growth & development*
  • Pluripotent Stem Cells / metabolism
  • Protein Binding
  • SOXE Transcription Factors / genetics
  • Signal Transduction


  • Alx4 protein, mouse
  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Homeodomain Proteins
  • SOXE Transcription Factors
  • Sox10 protein, mouse