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。DGC主要成员的流失 导致各种肌营养不良症，包括杜氏肌营养不良症（DMD），其中 dystrophin基因突变。许多DGC基因的突变，包括肌营养不良蛋白，也会导致神经系统疾病。 功能障碍，但这些变化的细胞和分子基础尚不清楚。我们正在探索新的 DGC成员的作用，包括肌营养不良蛋白和DGC中肌营养不良蛋白的关键结合伴侣， 细胞外基质受体肌营养不良蛋白聚糖，在发育中的脑室/脑室下区（V-SVZ），主要 控制出生后神经发生和神经胶质发生的前脑神经干细胞龛。我们最近 发现V-SVZ肌营养不良蛋白聚糖调节神经干细胞中的notch信号传导，以调节神经干细胞和神经细胞。 干细胞的命运决定，以及室管膜细胞的发育，专门的多纤毛细胞， 其围绕V-SVZ神经干细胞并且对于神经干细胞组织和功能是关键的。一个关键 在出生后的大脑发育过程中，V-SVZ的输出是少突胶质细胞祖细胞， 使前脑有髓鞘。我们最近还发现，肌营养不良蛋白聚糖和肌营养不良蛋白都影响 出生后脑发育过程中少突胶质细胞祖细胞的发育，包括延迟 白色物质束。在最近的研究结果的背景下，从肌肉领域表明，在缺乏 肌营养不良蛋白，notch信号在肌肉干细胞中受到干扰，我们提出肌营养不良蛋白也可能是一个关键， 在脑神经干细胞中的notch信号调节器，并在这样做时，可能会改变发育结果。在 第一个目的是我们将研究肌营养不良蛋白的不同同种型如何调节V-SVZ神经干细胞功能， 也就是说，神经元和神经胶质祖细胞的产生，以及生态位发育，即，发展， 成熟，室管膜细胞空间组织成V-SVZ生态位结构。在第二个目标中， 在出生后早期的大脑发育过程中，精确地靶向特定的V-SVZ细胞和时间，以了解 肌营养不良蛋白作用的细胞和时间基础以及其跨膜受体结合伴侣的作用， 肌营养不良聚糖在第三个目标中，我们将研究抗肌萎缩蛋白调节V-细胞中notch信号通路的能力。 SVZ神经干细胞，以及试图通过调节神经干细胞来拯救肌营养不良蛋白缺陷细胞表型。 notch途径，并确定在notch调控中肌营养不良蛋白-肌营养不良蛋白聚糖相互作用的作用。自始至终， 我们将使用DMD小鼠模型，如mdx 3cv（结合 notch活性报告小鼠），或遵循新生心室电穿孔策略以完全防止 在发育中的V-SVZ中肌营养不良蛋白的表达。此外，我们将评估抗肌萎缩蛋白在V-SVZ细胞中的功能。 模拟神经干细胞和室管膜细胞发育的培养物。这些研究将一起调查 肌营养不良蛋白在关键干细胞龛的形成和功能中的作用，因为它产生神经祖细胞， 出生后的大脑，并将提供深入了解如何dystrophin损失在DMD导致神经功能缺损。

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.