Neuron
Volume 89, Issue 1, 6 January 2016, Pages 83-99
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Article
Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain

https://doi.org/10.1016/j.neuron.2015.12.007Get rights and content
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Highlights

  • Mitotically delayed Magoh+/− radial glia directly produce altered progeny

  • Pharmacological prolonging of mitosis recapitulates Magoh+/− progenitor phenotypes

  • Prolonged progenitor mitosis causes increased neurogenic and apoptotic divisions

  • Apoptosis and differentiation are mutually exclusive outcomes of mitotic delay

Summary

Embryonic neocortical development depends on balanced production of progenitors and neurons. Genetic mutations disrupting progenitor mitosis frequently impair neurogenesis; however, the link between altered mitosis and cell fate remains poorly understood. Here we demonstrate that prolonged mitosis of radial glial progenitors directly alters neuronal fate specification and progeny viability. Live imaging of progenitors from a neurogenesis mutant, Magoh+/−, reveals that mitotic delay significantly correlates with preferential production of neurons instead of progenitors, as well as apoptotic progeny. Independently, two pharmacological approaches reveal a causal relationship between mitotic delay and progeny fate. As mitotic duration increases, progenitors produce substantially more apoptotic progeny or neurons. We show that apoptosis, but not differentiation, is p53 dependent, demonstrating that these are distinct outcomes of mitotic delay. Together our findings reveal that prolonged mitosis is sufficient to alter fates of radial glia progeny and define a new paradigm to understand how mitosis perturbations underlie brain size disorders such as microcephaly.

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