Wnt Signaling in Neural Crest Ontogenesis and Oncogenesis

Abstract

Neural crest (NC) cells are a temporary population of multipotent stem cells that generate a diverse array of cell types, including craniofacial bone and cartilage, smooth muscle cells, melanocytes, and peripheral neurons and glia during embryonic development. Defective neural crest development can cause severe and common structural birth defects, such as craniofacial anomalies and congenital heart disease. In the early vertebrate embryos, NC cells emerge from the dorsal edge of the neural tube during neurulation and then migrate extensively throughout the anterior-posterior body axis to generate numerous derivatives. Wnt signaling plays essential roles in embryonic development and cancer. This review summarizes current understanding of Wnt signaling in NC cell induction, delamination, migration, multipotency, and fate determination, as well as in NC-derived cancers.

Keywords: Wnt; neural crest stem cells; neural crest-derived cancer.

Figure 1

Anatomically distinct neural crest cell populations and their major derivates. Schematic lateral view of a mouse embryo at embryonic day 9.5 shows the cranial (green), vagal (azure), trunk (purple), and sacral (ruby) neural crest cells and their major derivatives. Vagal segment includes cardiac neural crest (indigo).

Figure 2

Wnt signaling regulates neural plate border (NPB) induction by regulating NPB specifiers. (A) NPB induction begins during gastrulation and is regulated by both canonical (orange) and non-canonical (blue) Wnts secreted from NPB and paraxial mesoderm. (B) Key components and possible interactions between Wnt signaling and NPB specifiers. NNE, non-neural ectoderm; NP, neural plate.

Figure 3

Wnt signaling induces neural crest cells by regulating NC specifiers. (A) NC is induced from the neural plate border at the end of gastrulation (zebrafish and Xenopus) or the beginning of neurulation (chick and mouse). This process is regulated by both canonical (orange) and non-canonical (blue) Wnts secreted from NPB, adjacent NNE, and paraxial mesoderm. (B) Key components and possible interactions between Wnt signaling and NC specifiers. NC, neural crest; NNE, non-neural ectoderm; NT, neural tube.

Figure 4

Bmp/Wnt signaling regulates trunk neural crest cell delamination. Undefined factors from somites inhibit Noggin (purple) expression anteriorly, creating a gradient Bmp (green) activity with a high level in anterior and low level in posterior of the dorsal neural tube. Bmp4, Yap, and RA signaling induce canonical Wnt1 expression, leading to Cyclin D1 transcription and G1/S transition to promote NC cell emigration. However, at the segmental plate mesoderm at the posterior region, Fgf signaling maintains high levels of Noggin that inhibits Bmp activity. Low Bmp activity blocks Wnt signaling, which prevents NC cell delamination from the caudal neural tube.

Figure 5

The role of Wnt signaling in CIL (contact inhibition of locomotion)-mediated directional migration of neural crest cells. Cell-cell interaction between NC cells localizes and activates Dsh (Dvl) at the cell membrane of the contact point, activating the small GTPase RhoA. The activation of RhoA is at least partly regulated by non-canonical Wnt signaling. RhoA inhibits Rac activity at the trailing edge of the cell, restricting a maximal Rac activation at the leading edge (green). Rac stimulates branched actin polymerization and drives the directed migration of NC cells.