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

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.

SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation

“…Although we have not observed any direct link between katanin and SPEF2, the phenotypic similarities suggest that they might function in the same pathway. Just like SPEF2, KATNB1 has been shown to interact with cytoplasmic dynein (Jin et al, 2017). However, while we showed that SPEF2 is likely to function downstream of dynein, KATNB1 has been shown to inhibit dynein motility, suggesting that it functions as an upstream regulator of dynein.…”

Genetics and mechanisms leading to human cortical malformations

“…Notably, patient mutations in KATNB1 were unable to elicit aster formation. In the same study, it was shown that p80 and/or NuMA down-regulation induces neural progenitors to exit the proliferation phase and prematurely commit to neuronal differentiation, in addition to delaying neuronal migration in the mouse embryonic brain [278].…”

“…Hu and col. [277] showed that patient-derived cells had decreased levels of both p80 and p60 proteins, as well as mitotic and signaling abnormalities. More recently, it was demonstrated that p80 regulates MT remodeling in combination with its interacting partner NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein, and that p80 is essential for aster formation and maintenance in vitro [278]. Notably, patient mutations in KATNB1 were unable to elicit aster formation.…”

“…An interesting study previously mentioned in section 3, focuses on the molecular bases of microcephaly and lissencephaly involving the gene KATNB1 (p80) [278]. In this work, brain organoids were generated from human iPSCs from microcephaly patients carrying mutations in this gene.…”

“…In this work, brain organoids were generated from human iPSCs from microcephaly patients carrying mutations in this gene. Mutant brain organoids showed fewer Tuj1+ neurons, and these neurons failed to migrate compared to controls [278]. Another interesting study involved the generation of patient-derived iPSCs to study the molecular bases of MDS, as previously mentioned, a severe LIS MCD characterized by nearly absent cortical folding often associated with reduced brain size, craniofacial dysmorphisms, ID and intractable epilepsy (see section 2.2.1) [298].…”