Abstract
ABSTRACTThe cerebral cortex contains an enormous number of neurons, allowing it to perform highly complex neural tasks. Understanding how these neurons develop at the correct time and place and in accurate numbers constitutes a major challenge. Here, we demonstrate a novel role for Gli3, a key regulator of cortical development, in cortical neurogenesis. We show that the onset of neuron formation is delayed in Gli3 conditional mouse mutants. Gene expression profiling and cell cycle measurements indicate that shortening of the G1 and S phases in radial glial cells precedes this delay. Reduced G1 length correlates with an upregulation of the cyclin-dependent kinase gene Cdk6, which is directly regulated by Gli3. Moreover, pharmacological interference with Cdk6 function rescues the delayed neurogenesis in Gli3 mutant embryos. Overall, our data indicate that Gli3 controls the onset of cortical neurogenesis by determining the levels of Cdk6 expression, thereby regulating neuronal output and cortical size.
Highlights
The ordered formation of neurons in sufficient numbers and at the correct time and place underlies the functioning of the cerebral cortex and its ability to perform highly complex neural tasks and to confer humans with their unique cognitive capabilities
Cortical neurogenesis is delayed in Gli3 mutant embryos To address which cortical progenitor cell types express Gli3 protein, we performed Gli3 double immunofluorescence staining with Pax6 and Tbr2 as markers for radial glial cells (RGCs) and basal progenitors (BPs), respectively, on sections of embryonic day (E) 12.5 cortex
We first determined the proportions of RGCs, BPs and cortical neurons in this region in E11.5 and E12.5 Gli3cKO embryos, i.e. at the beginning of cortical neurogenesis
Summary
The ordered formation of neurons in sufficient numbers and at the correct time and place underlies the functioning of the cerebral cortex and its ability to perform highly complex neural tasks and to confer humans with their unique cognitive capabilities. Central to generating appropriate numbers of neurons are cortical stem and progenitor cells and the control of their proliferation and differentiation rates. Changes in these parameters can have profound effects on cortical size and have been proposed to underlie cortical malformations in human disease as well as the expansion of the human cerebral cortex during evolution (Florio and Huttner, 2014). RGCs extend apical and basal processes and present with an apico-basal polarity (Götz and Huttner, 2005). They divide at the apical surface of the
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