RT Journal Article SR Electronic T1 GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 7791 OP 7805 DO 10.1523/JNEUROSCI.1309-12.2012 VO 32 IS 23 A1 Saiqun Li A1 Pierre Mattar A1 Dawn Zinyk A1 Kulwant Singh A1 Chandra-Prakash Chaturvedi A1 Christopher Kovach A1 Rajiv Dixit A1 Deborah M. Kurrasch A1 Yong-Chao Ma A1 Jennifer A. Chan A1 Valerie Wallace A1 F. Jeffrey Dilworth A1 Marjorie Brand A1 Carol Schuurmans YR 2012 UL http://www.jneurosci.org/content/32/23/7791.abstract AB The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors throughout corticogenesis, but is only required to specify early-born, deep-layer neuronal identities. Here, we examined how neuronal differentiation in general and Neurog2 function in particular are temporally controlled during murine neocortical development. We found that Neurog2 proneural activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. Accordingly, GSK3 activity, which is negatively regulated by canonical Wnt signaling, increases over developmental time, while Wnt signaling correspondingly decreases. When ectopically activated, GSK3 inhibits Neurog2-mediated transcription in cultured cells and Neurog2 proneural activities in vivo. Conversely, a reduction in GSK3 activity promotes the precocious differentiation of later stage cortical progenitors without influencing laminar fate specification. Mechanistically, we show that GSK3 suppresses Neurog2 activity by influencing its choice of dimerization partner, promoting heterodimeric interactions with E47 (Tcfe2a), as opposed to Neurog2–Neurog2 homodimer formation, which occurs when GSK3 activity levels are low. At the functional level, Neurog2–E47 heterodimers have a reduced ability to transactivate neuronal differentiation genes compared with Neurog2–Neurog2 homodimers, both in vitro and in vivo. We thus conclude that the temporal regulation of Neurog2–E47 heterodimerization by GSK3 is a central component of the neuronal differentiation “clock” that coordinates the timing and tempo of neocortical neurogenesis in mouse.