Figure 7. Dystroglycan guides the development and function of the SVZ neural stem cell niche.

(i) Ependymal cell development and niche maturation: ystroglycan loss-of-function leads to decreased expression of MCI, myb, and FoxJ1, transcription factors known to be suppressed by Notch and required for multiciliogenesis, suggesting a model in which dystroglycan suppression of Notch leads to increased MCI, myb, and FoxJ1, thereby promoting the development of multiciliated ependymal cells. And, dystroglycan-mediated remodeling of ependymal cell-associated ECM helps to regulate the organization of ependymal cells into niche pinwheels. Suppression of Notch activation rescues several of these defects in niche maturation following dystroglycan loss-of-function, placing Notch downstream of dystroglycan in this process. However dystroglycan can also influence MCI expression in a Notch-independent fashion via an unknown mechanism, indicated by the dashed green arrow. (ii) Oligodendrogenesis: The dystroglycan-deficient SVZ generates additional oligodendrogenic progenitor cells (oIPC) and oligodendrocyte progenitor cells (OPCs), and dystroglycan loss-of-function rapidly (i.e, within 6 hours) leads to elevated Notch signaling as well as elevated expression of Sox9, a pro-oligodendrogenic transcription factor downstream of Notch. Thus, as Notch normally promotes the development of oIPCs in the SVZ, our data also supports a model in which dystroglycan suppression of Notch in turn inhibits, or delays, oligodendrogenesis. (iii) Oligodendrocyte development: Dystroglycan-deficient brains display delayed myelination, despite an overabundance of oligodendrocytes in developing white matter, and dystroglycan loss-of-function in differentiating OPCs leads to elevated Notch signaling as well as elevated expression of Mash1 (which normally decreases as OPCs transition into oligodendrocytes). These data support a model in which oligodendroglial dystroglycan suppresses Notch signaling to help regulate timely myelination.