Hippo-Yap Pathway Orchestrates Neural Crest Ontogenesis

Abstract

Neural crest (NC) cells are a migratory stem cell population in vertebrate embryogenesis that can give rise to multiple cell types, including osteoblasts, chondrocytes, smooth muscle cells, neurons, glia, and melanocytes, greatly contributing to the development of different tissues and organs. Defects in NC development are implicated in many human diseases, such as numerous syndromes, craniofacial aberration and congenital heart defects. Research on NC development has gained intense interest and made significant progress. Recent studies showed that the Hippo-Yap pathway, a conserved fundamental pathway with key roles in regulation of cell proliferation, survival, and differentiation, is indispensable for normal NC development. However, the roles and mechanisms of the Hippo-Yap pathway in NC development remain largely unknown. In this review, we summarize the key functions of the Hippo-Yap pathway indicated in NC induction, migration, proliferation, survival, and differentiation, as well as the diseases caused by its dysfunction in NC cells. We also discuss emerging current and future studies in the investigation of the Hippo-Yap pathway in NC development.

Keywords: Hippo pathway; Yap and Taz; differentiation; migration; neural crest; proliferation.

FIGURE 1

The regulation of the Hippo-Yap pathway in neural crest (NC) development. At the stage of induction, Yap holds cells in NC progenitor state by regulating the expression of NC specifier genes, such as Pax3, Zic1, and Foxd3. After induction and specification, Yap potentially co-regulates G1/S transition with Wnt and BMP to promote pre-migratory NC cell EMT and delamination from the neural tube for migration. Meanwhile, glycolytic flux favors migration of NC cells through enhancing YAP1-TEAD1 interaction to drive the expression of EMT factors, such as Sox9, Ets1, and Zeb2 in chick embryos. Hippo-Yap pathway may also play a role in the regulation of BAF to NC migration in mouse embryos. In addition, Yap and Taz were found to promote proliferation and survival of NC cells which could be inhibited by Hippo kinases, Lats1/2. During NC differentiation, Yap65/Taz form a complex with Pax3 to promote melanocyte differentiation of NC cells by upregulating Mitf expression, which could be repressed by Hippo kinases Mst1 and Lats2. Yap overexpression favors glia cell fate of NC cells. Accordingly, Nf2 loss-of-function boosts the cell fate of glia at the expense of neurons. The complex of Yap/Taz-NICD promotes smooth muscle cell differentiation of NC cells by inhibiting the expression of Jagged1 (Created with Biorender.com).