Cell Type-Specific Transcriptional Control of Gsk3β in the Developing Mammalian Neocortex

Temporal control of neurogenesis is central for the development and evolution of species-specific brain architectures. The balance between progenitor expansion and neuronal differentiation is tightly coordinated by cell-intrinsic and cell-extrinsic cues. Wnt signaling plays pivotal roles in the proliferation and differentiation of neural progenitors in a temporal manner. However, regulatory mechanisms that adjust intracellular signaling amplitudes according to cell fate progression remain to be elucidated. Here, we report the transcriptional controls of Gsk3 beta, a critical regulator of Wnt signaling, in the developing mouse neocortex. Gsk3 beta expression was higher in ventricular neural progenitors, while it gradually declined in differentiated neurons. We identified active cis-regulatory module (CRM) of Gsk3 beta that responded to cell type-specific transcription factors, such as Sox2, Sox9, and Neurogenin2. Furthermore, we found extensive conservation of the CRM among mammals but not in non-mammalian amniotes. Our data suggest that a mammalian-specific CRM drives the cell type-specific activity of Gsk3 beta to fine tune Wnt signaling, which contributes to the tight control of neurogenesis during neocortical development.

Automated summary

Temporal control of neurogenesis is crucial for the development and evolution of brain structures. The balance between progenitor expansion and neuronal differentiation is tightly coordinated by cell-intrinsic and cell-extrinsic cues. Wnt signaling plays a key role in the proliferation and differentiation of neural progenitors, but the regulatory mechanisms adjusting intracellular signaling amplitudes are not fully understood.