Characterizing human-specific expression of ZP2 in the cerebellum

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SUMMARY Finding new treatments for neuropsychiatric disorders is a priority, as these disorders affect over 1 in 5 US adults and cost the US health care system over 180 billion dollars annually. Challenges limiting the pursuit of new treatments include 1) issues associated with using animals to model higher cognitive behaviors and 2) the implication of disparate brain regions that, when disrupted, manifest in diverse symptoms in motor, affective, and cognitive domains. To address these issues, this proposal will characterize the expression and deletion-associated phenotypes of a gene, ZP2, that exhibits human-specific expression in the cerebellum. The cerebellum has recently been implicated in coordinating higher cognitive functions, and its disruption has been associated not only with motor but also with cognitive and affective symptoms. In a comprehensive transcriptomic study of the brain, examining differential gene expression between humans and primates, the Sestan lab discovered that ZP2, a protein canonically involved in stabilizing the extracellular matrix and preventing polyspermy at the mammalian oocyte, is also uniquely expressed in human cerebellum. This proposal will investigate a potential analogous role of ZP2 at the granule cell dendrite, where it is hypothesized that ZP2 anchors and guides mossy fiber interactions during synaptogenesis and development. To do so, this proposal includes utilizing postnatal post-surgical and post-mortem human brain tissue and differentiated human induced pluripotent stem cells as a model system to localize ZP2 expression, determine ZP2 binding partners, and determine whether ZP2 is mechanistically implicated in the development of synapses between cerebellar granule cells and mossy fibers. This work has the potential to shed light on mechanisms of synaptic development that may be unique to humans and a potential molecular target for human-specific cognitive functioning localized to the cerebellum. This application also includes a training plan that will prepare the applicant for a career investigating neurodevelopmental disorders as a clinician-scientist.