Mechanisms underlying Joubert syndrome related brain malformations

描述(由申请人提供)：人类纤毛功能障碍会导致严重的大脑异常和认知障碍。然而，人们对这种被称为纤毛病的疾病中大脑畸形的分子机制知之甚少。Arl13b和INPP5E的隐性突变会导致Joubert综合征和相关疾病(JSRD)，这是一种人类纤毛疾病，由一种特定的后脑异常定义，即磨牙牙征。在这里，我们建议使用JSRD导致基因(Arl13b，Inpp5e)的小鼠模型及其导致JSRD的人类突变来系统地描述JSRD脑畸形的机制基础。为了实现这一目标，我们将从功能上表征由Arl13b，INPP5E基因突变引发的导致后脑异常的纤毛依赖或纤毛非依赖的信号机制。这项工作的结果将确定初级纤毛信号在神经元发育和连接中的作用。重要的是，分子级联和神经发育通路的描述将使我们能够设计出这些大脑疾病的最佳诊断和治疗策略。分子级联和神经发育通路的中断与纤毛疾病中脑畸形的发展密切相关。

DESCRIPTION (provided by applicant): Disrupted cilia function in humans results in profound brain abnormalities and cognitive impairments. However, little is known about the molecular mechanisms underlying the brain malformation in this class of disease, called ciliopathies. Recessive mutations in ARL13B and INPP5E cause Joubert Syndrome and Related Disorders (JSRD), a human ciliopathy defined by a specific hindbrain abnormality, the molar tooth sign. Here, we propose to use mouse models of JSRD causing genes (Arl13b, Inpp5e) and their JSRD-causing human mutations to systematically delineate the mechanistic underpinnings of the brain malformations in JSRD. Towards this goal, we will functionally characterize the cilia-dependent or cilia-independent signaling mechanisms triggered by ARL13B, INPP5E gene mutations that lead to hindbrain abnormalities. The outcome of this work will define the role of primary cilia signaling during neuronal development and connectivity. Importantly, delineation of molecular cascades and neurodevelopmental pathways, whose disruptions are integrally related to the development of brain malformations in ciliopathies will enable us to devise optimal diagnostic and therapeutic strategies for these brain disorders.