The Role of STRAD-alpha in Cortical Development

描述（由申请人提供）：皮质发育对儿童和成人的适当脑功能至关重要，但在分子水平上对神经发生和细胞命运的调节机制仍知之甚少。了解神经元连接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。这项建议旨在确定一个关键的分子机制，指定细胞分化的时间和有丝分裂后的特点，在发展中的新皮层。我们以前进行了研究，以确定在皮层发育过程中控制极性的基因，并建立了LKB 1（也称为Par 4），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。我们现在专注于LKB 1的调节假激酶STRAD-alpha。缺乏STRAD-α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。它的特点是严重的原因不明的癫痫发作。我们在本申请中的关键假设是：STRAD-α通过独特地改变LKB 1活性和稳定性，部分地通过促进祖细胞分化的多个方面和发育皮质的有丝分裂后特征，显著地促进脑发育。在本申请中，我们建议 理解1）产前和2.）STRAD-α丢失对小鼠皮质发育模型的出生后影响。我们也会3）。通过STRAD-alpha对LKB 1进行调节，并了解这如何有助于LKB 1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功能丧失的方法来确定STRAD-α如何在发育中的大脑中促进LKB 1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.