BMPs signal alternately through a SMAD or FRAP–STAT pathway to regulate fate choice in CNS stem cells

Abstract

The ability of stem cells to generate distinct fates is critical for the generation of cellular diversity during development. Central nervous system (CNS) stem cells respond to bone morphogenetic protein (BMP) 4 by differentiating into a wide variety of dorsal CNS and neural crest cell types. We show that distinct mechanisms are responsible for the generation of two of these cell types, smooth muscle and glia. Smooth muscle differentiation requires BMP-mediated Smad1/5/8 activation and predominates where local cell density is low. In contrast, glial differentiation predominates at high local densities in response to BMP4 and is specifically blocked by a dominant-negative mutant Stat3. Upon BMP4 treatment, the serine-threonine kinase FKBP12/rapamycin-associated protein (FRAP), mammalian target of rapamycin (mTOR), associates with Stat3 and facilitates STAT activation. Inhibition of FRAP prevents STAT activation and glial differentiation. Thus, glial differentiation by BMP4 occurs by a novel pathway mediated by FRAP and STAT proteins. These results suggest that a single ligand can regulate cell fate by activating distinct cytoplasmic signals.

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

“…Propagating NPCs with LIF and EGF, but without FGF2, promoted glial commitment and expansion and resulted in efficient APC fate specification within 6 wk (33)(34)(35)(36). A number of methodologies derive astroglia from pluripotent cells with varying levels of function and purity (37)(38)(39)(40).…”

TGF-β, Neuronal Stem Cells and Glioblastoma

“…In the latter case, whether ELF would play any role remains to be elucidated. Defined signaling pathways remain accessible to stem cells throughout development (Tsai and McKay, 2000;Panchision et al, 2001;Rajan et al, 2003), challenging these cells to make choices regarding fate and self-renewal (Hitoshi et al, TGF-b, NSCs and glioblastoma N Golestaneh and B Mishra 2002;Panchision and McKay, 2002). The direction of tumor development may be determined by the age of the NSCs, among other factors.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…LIF-induced astrogliogenesis generates more immature GFAPpositive progenitor cells, whereas BMP signaling promotes more mature GFAP-positive astrocytes that lack stem/progenitor cell properties (Bonaguidi et al 2005). BMP-mediated astroglial fate commitment can also occur by noncanonical STAT signaling through the serine-thre-onine kinase FKBP12/rapamycin-associated protein (FRAP), also known as mammalian target of rapamycin (mTOR), in high-density conditions (Rajan et al 2003). In this signaling pathway, FKBP12 binds to BMPRIA and after BMP-4 binding, detaches to activate FRAP, which in turn phosphorylates STAT causing astrocytic gene expression.…”