The ubiquitin ligase mLin41 temporally promotes neural progenitor cell maintenance through FGF signaling

Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO 80045, USA.
Genes & development (Impact Factor: 10.8). 04/2012; 26(8):803-15. DOI: 10.1101/gad.187641.112
Source: PubMed


How self-renewal versus differentiation of neural progenitor cells is temporally controlled during early development remains ill-defined. We show that mouse Lin41 (mLin41) is highly expressed in neural progenitor cells and its expression declines during neural differentiation. Loss of mLin41 function in mice causes reduced proliferation and premature differentiation of embryonic neural progenitor cells. mLin41 was recently implicated as the E3 ubiquitin ligase that mediates degradation of Argonaute 2 (AGO2), a key effector of the microRNA pathway. However, our mechanistic studies of neural progenitor cells indicate mLin41 is not required for AGO2 ubiquitination or stability. Instead, mLin41-deficient neural progenitors exhibit hyposensitivity for fibroblast growth factor (FGF) signaling. We show that mLin41 promotes FGF signaling by directly binding to and enhancing the stability of Shc SH2-binding protein 1 (SHCBP1) and that SHCBP1 is an important component of FGF signaling in neural progenitor cells. Thus, mLin41 acts as a temporal regulator to promote neural progenitor cell maintenance, not via the regulation of AGO2 stability, but through FGF signaling.

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    • "Moreover, the ectopic overexpression of mLin41 reduced the level of endogenous Ago2 in embryonic carcinoma cells and this effect was attenuated by inhibition of the proteasome with MG132. However, more recent studies put into question the control of AGO2 stability by mLIN41 (Chang et al., 2012; Chen et al., 2012). In particular, it was shown that mLin41 promotes neuronal progenitor cell maintenance through FGF signaling by ubiquitylation of Shc SH2-binding protein 1 (SHCBP1), but not via the regulation of AGO2 stability (Chen et al., 2012). "
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