This grant examines the role of Notch signaling in cerebellar cell specification. Here we investigate how Notch signaling contributes to the emergence of discrete cerebellar proliferative zones which in turn generate specific subsets of cerebellar cells. In this regard, we present a hypothesis of how Notch signaling acts in this process and investigate how antagonism between Notch and Math1 signaling contribute to the establishment and maintenance of the rhombic lip versus the main cerebellar ventricular zone. Central to this model is an examination of how Notch and BMP signaling interact in modulating Math1 expression during early cerebellar development. Work from genetic and gain-of-function analysis suggests that BMP signaling directs cerebellar progenitors to express Math1 and join the rhombic lip. We suggest that Notch signaling modulates this process by making cerebellar cells deaf to BMP inductive signals, thus maintaining progenitors in the main cerebellar ventricular zone. It is notable in this regard that constitutive Notch signaling results in progenitors becoming Bergmann radial glia. Based on both our own previous work in the forebrain, and work by others, radial glia may represent a stem cell population. Our preliminary work suggests that the same is true in the cerebellum. In this regard, we have shown that pluripotent progenitors exist in the cerebellum throughout embryonic development and that they express the radial glial marker BLBP. We will apply in vitro and in vivo methods to see if like in the forebrain Notch activation bestows stem cell potential on cerebellar cells. To complement this approach we will look at whether endogenous cerebellar radial glia possess stem cell properties, by doing a parallel examination of cerebellar radial glia isolated by their expression of GFP whose expression is directed by a BLBP promoter. To extend these studies, we also propose to fate map endogenous cerebellar radial glial using a genetic approach. In the long term our goal is to investigate whether the cerebellum has the capacity to undergo regeneration and whether we can use transplantation to augment neural repair in the cerebellum and more broadly the CNS in general.
Showing the most recent 10 out of 26 publications
