Essential role of non-canonical Wnt signalling in neural crest migration

Abstract

Migration of neural crest cells is an elaborate process that requires the delamination of cells from an epithelium and cell movement into an extracellular matrix. In this work, it is shown for the first time that the non-canonical Wnt signalling [planar cell polarity (PCP) or Wnt-Ca2+] pathway controls migration of neural crest cells. By using specific Dsh mutants, we show that the canonical Wnt signalling pathway is needed for neural crest induction, while the non-canonical Wnt pathway is required for neural crest migration. Grafts of neural crest tissue expressing non-canonical Dsh mutants, as well as neural crest cultured in vitro, indicate that the PCP pathway works in a cell-autonomous manner to control neural crest migration. Expression analysis of non-canonical Wnt ligands and their putative receptors show that Wnt11 is expressed in tissue adjacent to neural crest cells expressing the Wnt receptor Frizzled7 (Fz7). Furthermore, loss- and gain-of-function experiments reveal that Wnt11 plays an essential role in neural crest migration. Inhibition of neural crest migration by blocking Wnt11 activity can be rescued by intracellular activation of the non-canonical Wnt pathway. When Wnt11 is expressed opposite its normal site of expression, neural crest migration is blocked. Finally, time-lapse analysis of cell movement and cell protrusion in neural crest cultured in vitro shows that the PCP or Wnt-Ca2+ pathway directs the formation of lamellipodia and filopodia in the neural crest cells that are required for their delamination and/or migration.

Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

“…During development, FZD7-mediated tissue movement or cell migration involves non-canonical Wnt signalling. For example, neural crest cell migration in birds is mediated by Wnt11/FZD7 (De Calisto et al, 2005); and tissue separation (Winklbauer et al, 2001) and convergent extension movements (Djiane et al, 2000) during Xenopus gastrulation are via FZD7-mediated noncanonical Wnt/Ca 2 þ and Wnt/PCP pathways, respectively (reviewed in Kuhl, 2002;Tada et al, 2002). In contrast, FZD7-mediated tissue construction or epithelialization involves canonical Wnt signalling.…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Expression of Wnt11 and Wnt11R ligands was observed in the ectoderm next to premigratory NC cells just before the delamination in Xenopus (De Calisto et al, 2005;Garriock and Krieg, 2006). What's more, inhibition of Wnt11 through overexpression of dominant-negative construct leads to a complete inhibition of NC migration (De Calisto et al, 2005). In zebrafish, mutations of Stbm/trilobite (Jessen et al, 2002), Wnt11/silberblick (Heisenberg et al, 2000) or Wnt5/pipetail also causes a defect in directional NC migration (Rauch et al, 1997;Matthews et al, 2008).…”

“…Expression of Wnt11 and Wnt11R ligands was observed in the ectoderm next to premigratory NC cells just before the delamination in Xenopus (De Calisto et al, 2005;Garriock and Krieg, 2006). What's more, inhibition of Wnt11 through overexpression of dominant-negative construct leads to a complete inhibition of NC migration (De Calisto et al, 2005).…”

“…In zebrafish, mutations of Stbm/trilobite (Jessen et al, 2002), Wnt11/silberblick (Heisenberg et al, 2000) or Wnt5/pipetail also causes a defect in directional NC migration (Rauch et al, 1997;Matthews et al, 2008). Injections of dominant-negative Dishevelled inhibiting PCP signaling but not canonical Wnt signaling inhibit migration of NC cells in Xenopus (De Calisto et al, 2005) and severely disrupt the directional migration of NC cells in zebrafish (Matthews et al, 2008). In Xenopus and mice, expression of 'core PCP' components including Stbm/Vang, Prickle and DAAM was observed in the cranial NC (Bekman and Henrique, 2002;Darken et al, 2002;Goto and Keller, 2002;Nakaya et al, 2004).…”

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

“…It also has been established that Dvl functions in the non-canonical Wnt signalling pathway, which regulates polarised reorganisation of the actin cytoskeleton for cell motility in a β-catenin-independent manner [8][9][10] . The importance of the non-canonical Wnt signalling pathway has been established in gastrulation movements, dorsoventral patterning, neuronal migration, cochlear hair cell polarity, cardiogenesis and cancer progression [11][12][13][14][15][16][17][18] .…”