Investigating the Interactions Between Protocadherin-19 and Ryk and its Effect on Neurogenesis

Protocadherins are a large, diverse family of neural cell adhesion proteins, but their functions are not understood. Mutations or in several protocadherins have been associated with neurological disorders. For example, Protocadherin19 (PCDH19) causes epilepsy in females with mental retardation (EFMR). In this X chromosome-linked disease, girls randomly express one good allele or one mutant allele per cell due to a phenomenon known as X-linked inactivation. This mosaic expression leads to the symptoms classified as EFMR, but the effects on cellular pathways for the disease are not known. In zebrafish, the loss of Pcdh19 leads to the loss of columnar organization in the developing optic tectum through the loss of adhesion and an increase in neuronal proliferation and differentiation. The literature shows that Pcdh19 interacts with Ryk, a noncanonical Wnt receptor involved in neurogenesis. Based on previous data and the literature, we hypothesize that Pcdh19 binds to the extracellular domain of Ryk to inhibit binding of the Wnt3 ligand, preventing the intracellular domain of Ryk from being cleaved and translocated to the nucleus where it would initiate pathways for neuronal proliferation. Immunohistochemistry and co-immunoprecipitation were attempted to show if Pcdh19 affects cleavage of the Ryk intracellular domain, its nuclear translocation, and subsequent Wnt signaling. Transgenic and Ryk-knockout fish are being developed to perform experiments in vivo.School of Health and Rehabilitation Sciences Honors CommitteeUndergraduate Research Office Summer Funding AwardA three-year embargo was granted for this item.Academic Major: Biomedical Scienc