Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics

Sci Rep. 2017 Jan 12;7:39902. doi: 10.1038/srep39902.

Abstract

Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Dyneins / metabolism
  • Fibroblasts / physiology*
  • HeLa Cells
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Katanin / genetics
  • Katanin / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Microtubules / metabolism*
  • Mitosis / genetics
  • Mutation / genetics
  • Nervous System Malformations / genetics
  • Nervous System Malformations / metabolism*
  • Neurogenesis / genetics
  • Neurons / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Small Interfering / genetics

Substances

  • Katnb1 protein, mouse
  • Nuclear Proteins
  • Numa1 protein, mouse
  • RNA, Small Interfering
  • Adenosine Triphosphatases
  • katanin p80, human
  • Dyneins
  • Katanin