Protocadherin 19 in cortical development. (360G-Wellcome-109643_Z_15_Z)

Mutations in Pcdh19, a delta-2 protocadherin encoded on the X chromosome, lead to epilepsy with cognitive impairment in heterozygous females. The early disease onset suggests a neurodevelopmental basis for the disorder, but the function of this gene is entirely unknown. We propose to use the developing mouse brain to analyze early roles of Pcdh19 in neurogenesis, migration and circuit formation. Data from expression studies, anatomical analyses and the unusual inheritance mode of the disorder, w ith unaffected hemizygous males, support a role of Pcdh19 in these processes. We will first perform a comprehensive molecular and hodological characterization of Pcdh19 expressing cells at different developmental stages. We will then analyze a Pcdh19 null mouse mutant and assess whether neurogenesis and/or migration are affected. Using in utero electroporation, we will directly interfere with Pcdh19 function, either by shRNA to cause an acute reduction of its levels or with mutant forms of the p rotein. Synapse analysis in embryonic stem cell-derived neurons and electrophysiological recordings in brain slices will complete the analysis. Our results will provide insight into the roles of Pcdh19 during corticogenesis and form a useful basis for subsequent studies.