The Role of STRAD-alpha in Cortical Development

描述（由申请人提供）：皮层发育对儿童和成人的正常脑功能至关重要，但在分子水平上，神经发生和细胞命运调节的机制仍然知之甚少。了解神经元连接模式的机制对于理解它们在神经系统功能和功能障碍中的作用至关重要。本研究旨在确定发育中的新皮层中细胞分化和有丝分裂后特征的关键分子机制。我们之前已经进行了研究，以确定在皮质发育过程中控制极性的基因，并确定LKB1（也称为Par4），一种丝氨酸-苏氨酸激酶，是轴突-树突极性和细胞存活的关键调节因子。我们现在关注的是伪激酶strad - α对LKB1的调控。缺乏strad - α的人类患者患有羊水过多、大脑畸形和症状性癫痫（PMSE）综合征。它的特点是不明原因的严重的婴儿癫痫。我们在这项应用中的关键假设是：STRAD-alpha通过独特地改变LKB1的活性和稳定性，部分地促进祖细胞分化的多个方面和发育中的皮层的有丝分裂后特征，从而显著地促进大脑发育。在本应用程序中，我们建议

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.