Abnormalities in postnatal brain development as a feature of congenital muscular dystrophies

肌营养不良蛋白-糖蛋白复合物（DGC）对肌肉功能至关重要。主要DGC成员的损失

The dystrophin-glycoprotein complex (DGC) is critical for muscle function. The loss of key DGC members leads to a variety of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD) in which the dystrophin gene is mutated. Mutations in many DGC genes, including dystrophin, also cause neurological dysfunction, yet the cell and molecular basis of these changes are not understood. We are now exploring new roles for members of the DGC, including dystrophin and a key binding partner for dystrophin in the DGC, the extracellular matrix receptor dystroglycan, in the developing ventricular/subventricular zone (V-SVZ), the major neural stem cell niche of the forebrain that controls postnatal neurogenesis and gliogenesis. We recently discovered that V-SVZ dystroglycan modulates notch signaling in neural stem cells to regulate both neural stem cell fate decisions, as well as the development of ependymal cells, specialized multiciliated cells that surround V-SVZ neural stem cells and which are critical for neural stem cell organization and function. A key output of the V-SVZ during postnatal brain development is oligodendrocyte progenitor cells, which will go on to myelinate the forebrain. We have also recently found that dystroglycan and dystrophin both influence oligodendrocyte progenitor development during postnatal brain development, including delaying myelination in white matter tracts. In the context of recent findings from the muscle field that indicate that in the absence of dystrophin, notch signaling in perturbed in muscle stem cells, we propose that dystrophin may also be a key regulator of notch signaling in brain neural stem cells, and in doing so, may alter developmental outcomes. In the first aim we will examine how different isoforms of dystrophin regulates V-SVZ neural stem cell function, i.e., the production of neuronal and glial progenitors, as well as niche development, i.e., the development, maturation, and spatial organization of ependymal cells into V-SVZ niche structures. In the second aim we will precisely target particular V-SVZ cells and times during early postnatal brain development to understand the cell and temporal basis of dystrophin roles as well as the role of its transmembrane receptor binding partner, dystroglycan. In the third aim we will examine dystrophin’s ability to regulate the notch signaling pathway in V- SVZ neural stem cells, as well as attempt to rescue dystrophin-deficient cell phenotypes by modulation of the notch pathway and determine the role of dystrophin-dystroglycan interactions in notch regulation. Throughout, we will analyze stem cell niche phenotypes using DMD mouse models such as mdx3cv (in combination with notch activity reporter mice), or following neonatal ventricle electroporation strategies to completely prevent dystrophin expression in the developing V-SVZ. In addition we will assess dystrophin function in V-SVZ cell cultures that model neural stem cell and ependymal cell development. Together these studies will investigate dystrophin’s role in the formation and function of a crucial stem cell niche as it generates neural progenitors for the postnatal brain, and will provide insight into how dystrophin loss in DMD leads to neurological deficits.