DCX Domain Proteins and Microtubule Transport in Cerebral Cortical Development

描述(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连锁无脑综合征，这是一种X连锁的脑畸形，由大脑皮层发育过程中神经元的异常迁移引起，男性比女性更严重。由于目前尚不清楚这种罕见疾病的分子机制，靶向治疗至今仍不可用。最近的数据表明，DCX在神经元发育过程中是必需的，通过神经元特异性Kinesin-3马达KIF1A选择性地沿微管运输突触小泡前体。DCX定义了一类具有保守的微管结合域的微管相关蛋白(MAP)，选择性地促进KIF1A运动域与MT的结合，最有可能的是通过调节电机沿MT前进的运动过程中的运动动力学。这项建议的目的是在活细胞的背景下开发DCX、KIF1A和MT相互作用的工作模型。通过这些研究，我们将对神经元早期发育过程中基于MT的分子运动转运的基本机制有一个全面的了解。这项研究的具体目的是：1)建立依赖DCX的KIF1A介导的细胞内小泡运输的模型；2)开发人脑发育过程中小泡运输的MAP-Kinesin“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/或功能失效引起的各种神经发育障碍。 公共卫生相关性：双重皮质素(DCX)结构域蛋白是一个微管相关蛋白(MAP)家族，其特定的细胞功能尚不清楚，但最近的数据表明，在大脑发育的早期，它在调节动蛋白介导的囊泡运输方面具有潜在的作用。这项建议的目的是在活细胞的背景下建立DCX依赖的动蛋白功能的工作模型，并确定DCX结构域蛋白和其他分子马达图谱的特异性。这种基本的生物学洞察力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.