The Role of STRAD-alpha in Cortical Development

描述（由申请人提供）：皮质发育对于儿童和成人的正常大脑功能至关重要，但神经发生和细胞命运调节的机制在分子水平上仍然知之甚少。了解神经元连接模式的机制对于了解它们在神经系统功能和功能障碍中的作用至关重要。该提案旨在确定一个关键的分子机制，该机制指定了发育中的新皮质中细胞分化的时间和有丝分裂后的特征。我们之前进行了研究，以确定在皮质发育过程中控制极性的基因，并建立了 LKB1（也称为 Par4）（一种丝氨酸-苏氨酸激酶）作为轴突树突极性和细胞存活的关键调节因子。我们现在重点关注假激酶 STRAD-α 对 LKB1 的调节。缺乏 STRAD-alpha 的人类患者患有羊水过多、巨脑畸形和症状性癫痫 (PMSE) 综合征。其特征是不明原因的严重婴儿期癫痫。我们在此应用中的关键假设是：STRAD-alpha 通过独特地改变 LKB1 活性和稳定性，部分地促进祖细胞分化的多个方面和发育中皮层的有丝分裂后特征，从而显着促进大脑发育。在本申请中，我们建议 了解 1.) STRAD-alpha 缺失对小鼠皮质发育模型的产前和 2.) 产后影响。我们还将 3.) 探究 STRAD-alpha 对 LKB1 的调节，并了解这如何有助于 LKB1 活性的整体调节。然后，我们将在体外和体内使用功能获得和丧失的方法来确定 STRAD-α 如何促进发育中大脑中的 LKB1 功能。

DESCRIPTION (provided by applicant): Cortical development is critical to proper brain function in children and adults, but the mechanisms underlying the regulation of neurogenesis and cell fate remain poorly understood at the molecular level. Understanding the mechanisms patterning neuronal connections is essential to understanding their roles in nervous system function and dysfunction. This proposal aims to identify a critical molecular mechanism specifying the timing of cell differentiation and post-mitotic characteristics in the developing neocortex. We have previously undertaken studies to identify genes controlling polarity during cortical development and established LKB1 (also called Par4), a serine-threonine kinase, as a key regulator of both axon-dendrite polarity and cell survival. We now focus on the regulation of LKB1 by the pseudokinase STRAD-alpha. Human patients lacking STRAD-alpha suffer from a Polyhydramnios, Megalencephaly and Symptomatic Epilepsy (PMSE) syndrome. It is characterized by severe infantile-onset epilepsy of unknown origin. Our key hypothesis in this application is that: STRAD-alpha significantly contributes to brain development by contributing to multiple aspects of progenitor differentiation and post-mitotic characteristics of the developin cortex in part by uniquely altering LKB1 activity and stability. In this application, we propose to understand 1.) the prenatal and 2.) post-natal impact of STRAD-alpha loss in a murine model of cortical development. We will also 3.) pursue the regulation of LKB1 by STRAD-alpha and understand how this contributes to overall regulation of LKB1 activity. We will then use both gain- and loss-of-function approaches both in vitro and in vivo to determine how STRAD- alpha contributes to LKB1 function in the developing brain.