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.
Little is known about the cellular and molecular dysfunctions that lead to the emergence of brain abnormalities in ciliopathies such as Joubert Syndrome and related disorders (JSRD). However, the spectrum of neurobehavioral defects associated with primary cilia dysfunction in humans, suggest that primary cilia in neurons play critical and specific roles in the formation, maturation, and function of the cerebral cortex. Therefore, defining how disruptions in JSRD-causing genes (ARL13B, INPP5E) underly the brain malformations in JSRD will be essential to understand the pathogenic mechanisms of ciliopathies. This knowledge could help identify and rationalize novel targets for therapeutic interventions for cilia dysfunction-related brain disorders.