Molecular mechanisms of radial glia formation in the developing cerebellum.

摘要

The generation and migration of neurons are critical events during brain development. Both of these processes are tightly regulated and require a specialized cell type called the radial glial cell. Radial glia physically guide nascent neurons to their target destinations in the brain, and as such they are essential for central nervous system development.; In the cerebellum Bergmann radial glia act as a scaffold to support migrating granule neurons. It has been proposed that the formation of Bergmann glia is induced by contact with these neurons. However, the mechanisms involved in this process are not well understood. Using an in vitro system that mimics this neuronal-induced radial glia morphological differentiation, I have identified and characterized two signaling pathways that mediate this process.; My experiments show that the neuronal induction of radial glia formation is the result of sequential signaling through Notch1 and erbB receptors. First, Notch1 activation by neuronal contact induces transcription of the brain lipid binding protein (BLBP) and erbB2 genes in glia. The subsequent increase in erbB receptors makes the glia more responsive to neuronal neuregulin (NRG1), which then induces the morphological transformation into radial glia. Interestingly, two different signaling pathways mediate these effects of Notch1 on transcription. BLBP expression is dependent on Su(H), while erbB2 expression is independent of Su(H).; The finding that Notch1 signaling can induce radial glia morphological differentiation and erbB expression independent of Su(H), led me to examine further this signaling pathway. I identified Deltex1 (DTX1) as the co-regulator of Notch1 signaling that mediates these processes. I show that DTX1 mediates Notch1-induced erbB2 expression and subsequent radial glia morphological differentiation. These data also indicate that a hierarchical relationship exists between Su(H) and DTX1, since overexpression of DTX1 can inhibit Su(H)-dependent pathways, such as BLBP expression, but Su(H) cannot block DTX1-dependent pathways. Together, these results define the mechanisms by which Notch1 and erbB signaling regulate the formation of radial glia, an essential event in brain development.