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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.

A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development