Botch Promotes Neurogenesis by Antagonizing Notch

Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development. [Display omitted] ► Botch inhibits the S1 furin-like cleavage of Notch ► Botch likely interacts with Notch in the Golgi, leading to decreased Notch processing ► Botch inhibits Notch function and promotes neurogenesis in vitro and in vivo Chi et al. identify Botch as a developmentally regulated inhibitor of Notch that promotes neurogenesis both in vitro and in vivo. Botch inhibits the S1 furin-like cleavage of Notch, thus attenuating Notch maturation and cell-surface expression and helping to keep signaling in check.