The Role of STRAD-alpha in Cortical Development

描述(申请人提供)：皮质发育对儿童和成人正常的大脑功能至关重要，但神经发生和细胞命运的调节机制在分子水平上仍知之甚少。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是至关重要的。这一建议旨在确定一个关键的分子机制，指定细胞分化的时机和发育中的新皮质的有丝分裂后特征。我们之前已经进行了一些研究，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。我们现在关注的是假性激酶Strad-α对LKB1的调节。缺乏STRAD-α的人类患者会出现羊水过多、巨脑和症状性癫痫(PMSE)综合征。它的特点是病因不明的严重婴儿期癫痫。我们在这一应用中的关键假设是：STRAD-α通过促进发育中皮质的祖细胞分化和有丝分裂后特征的多个方面而显著促进大脑发育，部分是通过独特地改变LKB1的活性和稳定性。在本申请中，我们建议 了解1。)产前和2。)在小鼠皮质发育模型中，Strad-Alpha丢失对出生后的影响。我们还将3。)探索Strad-Alpha对LKB1的调节，并了解这如何有助于对LKB1活性的整体调节。然后，我们将在体外和体内使用获得和丧失功能的方法来确定Strad-Alpha如何在发育中的大脑中对LKB1功能做出贡献。

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.