A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development
Kerstin Hasenpusch-Theil,
Christine Laclef,
Matt Colligan,
Eamon Fitzgerald,
Katherine Howe,
Emily Carroll,
Shaun R Abrams,
Jeremy F Reiter,
Sylvie Schneider-Maunoury,
Thomas Theil
Affiliations
Kerstin Hasenpusch-Theil
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom
Christine Laclef
Sorbonne Université, CNRS UMR7622, INSERM U1156, Institut de Biologie Paris Seine (IBPS) - Developmental Biology Unit, Paris, France
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
Eamon Fitzgerald
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
Katherine Howe
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
Emily Carroll
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
Shaun R Abrams
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Jeremy F Reiter
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Chan Zuckerberg Biohub, San Francisco, United States
Sylvie Schneider-Maunoury
Sorbonne Université, CNRS UMR7622, INSERM U1156, Institut de Biologie Paris Seine (IBPS) - Developmental Biology Unit, Paris, France
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom
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.
