Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling

Abstract

Canonical Wnt signaling instructively promotes sensory neurogenesis in early neural crest stem cells (eNCSCs) (Lee, H.Y., M. Kléber, L. Hari, V. Brault, U. Suter, M.M. Taketo, R. Kemler, and L. Sommer. 2004. Science. 303:1020–1023). However, during normal development Wnt signaling induces a sensory fate only in a subpopulation of eNCSCs while other cells maintain their stem cell features, despite the presence of Wnt activity. Hence, factors counteracting Wnt signaling must exist. Here, we show that bone morphogenic protein (BMP) signaling antagonizes the sensory fate-inducing activity of Wnt/β-catenin. Intriguingly, Wnt and BMP act synergistically to suppress differentiation and to maintain NCSC marker expression and multipotency. Similar to NCSCs in vivo, NCSCs maintained in culture alter their responsiveness to instructive growth factors with time. Thus, stem cell development is regulated by combinatorial growth factor activities that interact with changing cell-intrinsic cues.

RETRACTED ARTICLE: Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences

“…Consequently, NCSC clones were pre-treated with Wnt1 and BMP2 for one week before inducing their differentiation [13]. Interestingly, those clones became then able to differentiate into adipocytes (Fig.…”

The disparate role of BMP in stem cell biology

“…Complementary to this, embryos expressing a constitutively active form of b-catenin specifically in NCSCs develop sensory neurons at the expense of virtually all other neural crest derivatives . Recently, BMPs have been shown to antagonize this Wnt response, but when added simultaneously with Wnt1 suppress all neural differentiation and maintain NCSC multipotency (Kleber et al, 2005). These data indicate that in NCSCs combined BMP and Wnt signals regulate self-renewal, whereas the individual factors alone promote specific lineage differentiation.…”

“…Wnts on the other hand direct NCSCs towards sensory neuronal fate . Surprisingly, unlike their individual activities, treating NCSCs with Wnt and BMP together maintains the cells in a pluripotent state (Kleber et al, 2005). Since Wnt pathway components interact physically with Smads (Labbe et al, 2000), this distinct response to concomitant activation may reflect unique cellular activities of this crosstalk.…”

Stage- and area-specific control of stem cells in the developing nervous system

“…those found in the sciatic nerve or the DRG) do not undergo sensory neurogenesis upon treatment with Wnt1. Similarly, NCSCs maintained in culture with Wnt1 and BMP2 cease to respond to Wnt1 promoting sensory neurogenesis [18]. Taken …”

“…During neural crest development, Wnt and BMP act synergistically on early, emigrating neural crest stem cells (eNCSC) to suppress differentiation and keep the cells in a multipotent stem cell state [18]. Wnt signaling on its own instructively promotes sensory neurogenesis in eNCSCs [19,20].…”