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Triplication of DSCAM impairs axon growth and guidance in Down syndrome

Kristy Welshhans, PhD, Biological Sciences, ºÚÁÏÍø

Down syndrome affects about 1 in every 700 infants, and is the most prevalent genetic cause of intellectual disability. Although multiple mouse models have been created, they are an imperfect recapitulation of this disorder. We are currently using a human neuronal model of Down syndrome, induced pluripotent stem cells (iPSCs), to more directly test our hypotheses regarding the mechanisms underlying dysregulated neuronal connectivity associated with this disorder. Down Syndrome Cell Adhesion Molecule (DSCAM) is a gene that is triplicated in Down syndrome and highly expressed in the developing nervous system. Furthermore, Dscam is both a cell adhesion molecule and axon guidance receptor that is involved in proper neuronal wiring. We have previously demonstrated that DSCAM overexpression in mouse primary neurons results in a decrease in axon outgrowth, which provides a strong rationale for DSCAM contributing to impaired connectivity formation in Down syndrome. Here we will use human iPSC-derived neurons in combination with live cell microscopy and CRISPR/Cas9 directed gene excision to better understand the contribution of DSCAM to Down syndrome. In summary, we will use a human model of Down syndrome to increase our understanding about altered neuronal connectivity underlying Down syndrome.