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Atypical PKC and Notch Inhibition Differentially Modulate Cortical Interneuron Subclass Fate from Embryonic Stem
David J Tischfield1, Junho Kim2, Stewart A Anderson1
1Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA; Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA.
Abstract:
Recent studies indicate that the location of neurogenesis within the medial ganglionic eminence (MGE) critically influences the fate determination of cortical interneuron subgroups, with parvalbumin (Pv) interneurons originating from subventricular zone divisions and somatostatin (Sst) interneurons primarily arising from apical divisions. The aPKC-CBP and Notch signaling pathways regulate the transition from apical to basal progenitor and their differentiation into post-mitotic neurons. We find that aPKC inhibition enhances intermediate neurogenesis from stem cell-derived MGE progenitors, resulting in a markedly increased ratio of Pv- to Sst-expressing interneurons. Conversely, inhibition of Notch signaling enriches for Sst subtypes at the expense of Pv fates. These findings confirm that the mode of neurogenesis influences the fate of MGE-derived interneurons and provide a means of further enrichment for the generation of specific interneuron subgroups from pluripotent stem cells.