Non-coding RNA regulation of early neural development

神经上皮祖细胞自我更新和分化缺陷可导致深刻的神经发育 疾病包括破坏性的出生缺陷，如小头畸形。建议的长远目标 研究是为了了解神经上皮祖细胞的自我更新和分化是如何协调的。这 该提案特别关注小鼠早期表达的一种长的非编码RNA(LncRNA) 神经上皮祖细胞，随着分化的进行，lncRNA转录本被处理以产生 参与神经元分化的微RNA。此外，lncRNA在物理上与key相互作用 小头畸形蛋白，但lncRNA和这些蛋白之间的功能关系尚不清楚。这个 三个目标涉及的主要问题如下。目标1将检验lncRNA功能的假设 -不依赖于miRNA-in调节神经上皮祖细胞的增殖和存活。目标1创建 具有特定缺失突变的细胞系和小鼠模型，包括在 一位小头畸形患者，用于功能研究。目标2将探索潜在的细胞机制 小头畸形表型，初步数据显示有丝分裂停滞。此外，目标2将解决 假设lncRNA作为一种支架，通过其 与粘附素复合体的相互作用，这也与小头畸形症有关。目标3将探索 LncRNA宿主转录本和嵌入转录本之间时空差异的机制 MiRNA。我们的总体目标是发现协调神经上皮祖细胞的新机制 增殖和分化，以及破译这种未被探索的lncRNA如何机械地作用于 正常的大脑发育。利用神经上皮祖细胞的潜力有望治疗 神经元损伤和神经退行性疾病，以及神经上皮祖细胞功能障碍是根源 许多神经疾病的病症。我们的研究将提供一种新的lncRNA和 已知的小头畸形蛋白，极大地扩展了我们对这种严重的大脑疾病的认识。

Defects in neuroepithelial progenitor self-renewal and differentiation can result in profound neurodevelopmental disorders including devastating birth defects such as microcephaly. The long-term objective of the proposed studies is to understand how neuroepithelial progenitor cell self-renewal and differentiation are coordinated. This proposal specifically focuses on a long non-coding RNA (lncRNA) that is expressed early in mouse neuroepithelial progenitor cells and, as differentiation proceeds, the lncRNA transcript is processed to yield a microRNA that is involved in neuronal differentiation. Moreover, the lncRNA physically interacts with key microcephaly proteins but the functional relationship between the lncRNA and these proteins is unknown. The major questions addressed in three Aims are as follows. Aim 1 will test the hypothesis that the lncRNA functions - independent of the miRNA - in regulating neuroepithelial progenitor proliferation and survival. Aim 1 creates cell lines and mouse models with specific deletion mutations, including a small deletion of this locus observed in a patient with microcephaly, for functional studies. Aim 2 will explore the cellular mechanism underlying the microcephaly phenotype, preliminary data which suggests a mitotic arrest. Moreover, Aim 2 will address the hypothesis that the lncRNA functions as a scaffold to help maintain sister chromatid cohesion through its interactions with the Cohesin complex, which is also implicated in microcephaly. Aim 3 will explore the mechanism underlying the temporal-spatial difference between the lncRNA host transcript and the embedded miRNA. Our overall goal is to discover new mechanisms that coordinate neuroepithelial progenitor cell proliferation and differentiation, as well as to decipher how this unexplored lncRNA mechanistically acts to allow normal brain growth. Harnessing the potential of neuroepithelial progenitor cells holds promise for the treatment of neuronal injury and neurodegenerative diseases, and dysfunction of neuroepithelial progenitors is at the root of numerous neurological disorders. Our studies will provide mechanistic links between a novel lncRNA and known microcephaly proteins to greatly extend our knowledge of this profound brain disorder.