title: Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Louis-Jan
authors.initials: LJ
authors.lastname: Pilaz
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: McMahon
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Miller
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Lennox
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Aussie
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Salmon
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: debra.silver@duke.edu.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Silver
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D008822:Mice, Transgenic; D008938:Mitosis / Q000235:genetics*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000166:cytology*