Cell-autonomous Jagged1 signaling as a mediator of neural stem cell differentiation

• Applicant: Professor Verdon Taylor, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 87528965

Like the embryonic nervous system, the adult mammalian brain contains stem cell-like cells but displays a low capacity for neuronal regeneration. Thus, injuries or diseases that result in a loss of neurons are particularly debilitating. Understanding how neurogenesis is controlled during development may provide important clues about how to improve regeneration in the brain. The regulation of neural progenitor cell maintenance and fate during development of the mammalian nervous system require a precise interplay between extrinsic cues and cell intrinsic programs. Dialog between neural progenitors and their local environment or niche is central to these processes. Notch1 signaling is critical for embryonic development in mice and required to maintain multipotent neural stem cells (NSCs). Notch1 is a receptor for the transmembrane protein Jagged1. We have shown that Jagged1 is also a key regulator of neural development and NSCs maintenance (Nyfeler et al., 2005; Weller et al., 2006). Both Notch1 and Jagged1 are prominent components of the adult neurogenic niches and play roles in maintaining NSC (Nyfeler et al., 2005). We have identified a novel function for Jagged1 in regulating neurogenesis by inducing a cell-intrinsic signal to the nucleus of the Jagged1-presenting niche cells. We show that upon activation, Jagged1 is sequentially cleaved by secretases releasing the intracellular domain (JagICD) into the cell. We have identified components of this novel JagICD signal and obtained initial data addressing the cellular function of this cell-autonomous Jagged1 signal. We will use transgenic mice to study this novel signal in NSC maintenance and differentiation in vivo. The elucidation of the bilateral signals during neurogenesis will greatly facilitate our understanding of the mechanisms controlling NSC differentiation, and the Jagged1- mediated cell autonomous signals may define new targets for therapeutic intervention in brain repair.

• DFG Programme: Research Grants
• International Connection: Switzerland