Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis

Abstract

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., The dry eye disease caused by lacrimal gland dysgenesis is one of the most common ocular ailments. In this study, we show that Shp2 mediates the sequential use of FGF signaling in lacrimal gland development. Our study identifies Alx4 as a novel target of Shp2 signaling and a causal gene for lacrimal gland aplasia in humans. Given this result, there may also be a potential role for Alx4 in guiding pluripotent stem cells to produce lacrimal gland tissue. Finally, our data reveals an Alx4-Fgf10 regulatory unit broadly conserved in the diverse array of terrestrial animals from humans to reptiles, but not in aquatic animals such as amphibians and fish, which sheds light on how the lacrimal gland arose as an evolutionary innovation of terrestrial animals to adapt to their newfound exposure to an airy environment.