Abstract
During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.
Highlights
Building a functional cerebral cortex which confers humans with their unique cognitive capabilities requires controlling the proliferation of neural progenitor cells and the timing and modes of neurogenic cell divisions
We first considered the possibility that such early patterning defects may be present in Inpp5e mutant embryos and could affect cortical stem cell development
Basal progenitors were not affected (Fig. 8G, H, J, K). These findings indicate that re-introducing a single copy of the Gli3 repressor form (Gli3R) allele into the Inpp5e mutant background leads to a partial rescue of cortical neurogenesis in Inpp5e embryos whereas two copies are required for a full rescue
Summary
Building a functional cerebral cortex which confers humans with their unique cognitive capabilities requires controlling the proliferation of neural progenitor cells and the timing and modes of neurogenic cell divisions. Varying the timing and modes of neurogenesis affects neuronal numbers and subtype composition of the cortex (Florio & Huttner, 2014). RGCs generate neurons in two ways, either directly or indirectly via the production of basal progenitors (BPs) that settle in the subventricular zone (SVZ) and express the Tbr transcription factor (Englund et al, 2005). The majority of BPs divide once to produce two neurons whereas the remainders undergo one additional round of symmetric proliferative division before differentiating into two neurons
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