Non-Canonical Wnt-Signaling through Ryk Regulates the Generation of Somatostatin- and Parvalbumin-Expressing Cortical Interneurons

GABAergic interneurons have many important functions in cortical circuitry, a reflection of their diversity as a cell population. However, the developmental origins of this diversity are poorly understood. Here, we identify a rostral-caudal gradient of Wnt-responsiveness that delineates the specification of the two main interneuron subclasses. Caudallysituated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. Parvalbumin (PV)-expressing basket cells, by contrast, originate mostly from the rostral MGE where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through beta-catenin, Wnt signaling transmitted via the non-canonical receptor, Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain-of-function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting Ryk signaling acts in a graded fashion. These data reveal a complex and important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of mature cortical interneuron subtypes.