DCX Domain Proteins and Microtubule Transport in Cerebral Cortical Development

描述（由申请人提供）：Doublecortin（DCX）是大脑皮层神经元迁移的关键调节因子。DCX蛋白功能缺陷导致双皮质/X连锁无脑畸形综合征，这是一种由大脑皮质发育期间神经元异常迁移引起的X连锁脑畸形，严重影响男性而非女性。由于这种罕见疾病的分子机制目前还不清楚，因此迄今为止还没有靶向治疗方法。最近的数据表明，DCX是需要在神经元发育过程中的选择性运输突触囊泡前体沿着微管（MT）的神经元特异性驱动蛋白-3马达KIF 1A。DCX定义了一类具有保守微管结合结构域的微管相关蛋白（MAP），它选择性地促进KIF 1A马达结构域与MT的结合，最有可能是通过在马达沿着MT进行性运动期间调节马达动力学。本提案的目的是开发一个工作模型的DCX，KIF 1A，和MT的活细胞的背景下的相互作用。通过这些研究，我们将获得一般的洞察力的基本机制，管理MT为基础的分子马达运输在早期神经元的发展。本研究的具体目的是：1）开发细胞内DCX依赖性KIF 1A介导的囊泡转运模型; 2）开发人脑发育过程中囊泡转运的MAP-驱动蛋白“代码”。从这些研究中获得的见解将有助于设计和开发新的基于机制的治疗策略，用于治疗由DCX结构域蛋白的结构和/或功能故障引起的各种神经发育障碍。 公共卫生相关性：双皮质素（DCX）结构域蛋白是微管相关蛋白（MAP）的一个家族，其特定的细胞功能尚不清楚，但最近的数据表明其在早期脑发育期间调节驱动蛋白介导的囊泡运输中的潜在作用。该提案旨在开发活细胞背景下DCX依赖性驱动蛋白功能的工作模型，并确定DCX结构域蛋白和其他MAPs对分子马达的特异性。这种基本的生物学见解将允许设计和开发新的基于机制的治疗策略，用于治疗由DCX结构域蛋白的结构和/或功能故障引起的各种神经发育障碍。

DESCRIPTION (provided by applicant): Doublecortin (DCX) is a key regulator of neuronal migration in the cerebral cortex. Defects of DCX protein function result in double cortex/X-linked lissencephaly syndrome, an X-linked brain malformation resulting from aberrant migration of neurons during development of the cerebral cortex, severely affecting males over females. Targeted therapeutics are unavailable to date as the molecular mechanisms underlying this rare disorder are presently not understood. Recent data show that DCX is required during neuronal development for selective transport of synaptic vesicle precursors along microtubules (MTs) by the neuron-specific kinesin-3 motor KIF1A. DCX, which defines a class of microtubule-associated proteins (MAPs) with conserved microtubule binding domains, selectively facilitates binding of the KIF1A motor domain to the MT, most likely through regulation of motor dynamics during processive movement of the motor along the MT. The objective of this proposal is to develop a working model of the interactions of DCX, KIF1A, and the MT within the context of the live cell. Through these studies we will gain general insight into the basic mechanisms governing MT-based molecular motor transport during early neuronal development. The specific aims of this study are to: 1) Develop a model for DCX-dependent KIF1A-mediated vesicle transport within a cellular context; and 2) Develop a MAP-kinesin "code" for vesicular transport during human brain development. The insights obtained from these studies will facilitate the design and development of novel mechanism-based therapeutic strategies for the treatment of a variety of neurodevelopmental disorders caused by structural and/or functional failure of DCX domain proteins. PUBLIC HEALTH RELEVANCE: Doublecortin (DCX) domain proteins are a family of microtubule-associated proteins (MAPs) whose specific cellular functions are not well understood, but recent data suggests a potential role in regulating kinesin- mediated vesicle transport during early brain development. This proposal aims at developing a working model of DCX-dependent kinesin function within the context of the live cell, and determining the specificity of DCX domain proteins and other MAPs for molecular motors. Such basic biological insight will allow the design and development of novel mechanism-based therapeutic strategies for the treatment of a variety of neurodevelopmental disorders caused by structural and/or functional failure of DCX domain proteins.