Mechanisms underlying Joubert syndrome related brain malformations

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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.