Germ cell nuclear factor (Gcnf/Nr6a1) plays a novel role in neural crest cell induction

Abstract

The neural crest (NC) is a multipotent, migratory cell population that is a hallmark of vertebrate evolution and gives rise to a diverse array of tissues including peripheral nervous system and craniofacial skeleton. Formation of the NC encompasses several steps including induction and specification, epithelial to mesenchymal transition (EMT), migration and differentiation into diverse cell types. Previous work in aquatic and avian systems revealed that Wnt, BMP and FGF signaling pathways drive NC formation. However, knockout mouse models failed to recapitulate a role for these pathways in mammalian NC induction. Our approach uses a mouse mutant in germ cell nuclear factor (Gcnf)/Nr6a1, to study mammalian NC formation. Our analysis of Gcnf−/− embryos revealed a total absence of NC posterior to the first branchial arch and a great anterior reduction in cranial NC. Both phenotypes result from a failure of neural progenitors to differentiate into NC and undergo EMT. Along with our global gene expression and protein interaction analysis, we show that Gcnf regulates two key processes during NC formation: stem cell maintenance and EMT. Therefore, we hypothesize that Gcnf acts as a bimodal switch (i) repressing pluripotency genes and activating NC‐specific genes and (ii) regulating EMT during NC delamination. This is the first example of a total loss of NC in a specific domain of the neuraxis in a mammalian system.Grant Funding Source: AAA Postdoctoral Fellowship