Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis.

TitleAlx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis.
Publication TypeJournal Article
Year of Publication2017
AuthorsGarg A, Bansal M, Gotoh N, Feng G-S, Zhong J, Wang F, Kariminejad A, Brooks S, Zhang X
JournalPLoS Genet
Date Published2017 Oct
KeywordsAnimals, Apoptosis, Cell Differentiation, Cell Lineage, Fibroblast Growth Factor 10, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Lacrimal Apparatus, Mesoderm, Mice, Morphogenesis, Neural Crest, Pluripotent Stem Cells, Protein Binding, Signal Transduction, SOXE Transcription Factors

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.

Alternate JournalPLoS Genet.
PubMed ID29028795
PubMed Central IDPMC5656309
Grant ListR01 EY022409 / EY / NEI NIH HHS / United States
R01 NS099568 / NS / NINDS NIH HHS / United States