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

营养不良蛋白-糖蛋白复合体(DGC)对肌肉功能至关重要。DGC关键成员的流失 导致多种肌营养不良，包括杜氏肌营养不良症(DMD) 肌营养不良蛋白基因发生突变。许多DGC基因的突变，包括营养不良蛋白，也会导致神经性疾病 功能障碍，但这些变化的细胞和分子基础尚不清楚。我们现在正在探索新的 DGC成员的角色，包括dystrophin和dystrophin在DGC中的关键结合伙伴， 在发育中的室/室下区(V-SVZ)，主要的细胞外基质受体DystroGan 前脑中控制出生后神经发生和神经胶质发生的神经干细胞利基。我们最近 发现V-SVZ营养不良多糖调节神经干细胞中的Noch信号以调节两个神经元 干细胞命运的决定，以及室管膜细胞的发育，特化的多纤毛细胞 包围V-SVZ神经干细胞，它们对神经干细胞的组织和功能至关重要。一把钥匙 V-SVZ在出生后大脑发育过程中的输出是少突胶质前体细胞，它将继续 使前脑形成髓鞘。我们最近还发现，抗肌营养不良蛋白和抗肌营养不良蛋白都会影响 少突胶质细胞前体细胞在出生后脑发育过程中的发育，包括延迟脑内髓鞘形成 白质束。在肌肉领域的最新发现表明，在缺乏 肌营养不良蛋白、缺口信号在肌肉干细胞中的紊乱，我们认为肌营养不良蛋白也可能是一个关键 大脑神经干细胞中Notch信号的调节者，在这样做的过程中，可能会改变发育结果。在……里面 第一个目标，我们将研究不同亚型的dystrophin如何调节V-SVZ神经干细胞功能， 即神经元和神经胶质前体细胞的产生，以及利基发育，即发育， 室管膜细胞成熟，并在空间上组织成V-SVZ壁龛结构。在第二个目标中，我们将 精确定位特定的V-SVZ细胞和出生后早期脑发育的时间，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伙伴的作用， 营养不良葡聚糖。在第三个目标中，我们将研究dystrophin对V-TRAIL中Noch信号通路的调节能力。 SVZ神经干细胞，以及试图通过调节Dystrophin缺陷细胞表型来挽救Dstrophin缺陷细胞表型 Notch途径，并确定dystrophin-dystroglan相互作用在Notch调节中的作用。自始至终， 我们将使用诸如mdx3cv(结合 Notch活动报告小鼠)，或遵循新生儿脑室电穿孔策略完全防止 营养不良蛋白在发育中的V-SVZ中的表达。此外，我们还将评估V-SVZ细胞中的抗肌营养不良蛋白功能 模拟神经干细胞和室管膜细胞发育的培养。这些研究将共同调查 抗肌营养不良蛋白在关键干细胞巢的形成和功能中的作用 并将提供对DMD中Dstrophin丢失如何导致神经功能障碍的洞察。

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.