Cdk1 Activates Pre-mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem Cells

Baffet, Alexandre D.; Hu, Daniel Jun-Kit; Vallee, Richard B.

doi:10.1016/j.devcel.2015.04.022

Cited by 93 publications

(161 citation statements)

References 58 publications

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“…Studies in rodents have shown that this protein plays an important role in dynein-based cargo transport in neurons (32)(33)(34). Consistent with these findings, missense mutations in the human BICD2 gene are also associated with SMALED (35)(36)(37) and cortical malformations (38,39).…”

Section: Significancesupporting

confidence: 71%

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

Hoang

Schlager

Carter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4-MDa motor complex that traffics organelles, vesicles, and macromolecules toward microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterize 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor Bicaudal-D2 (BICD2). Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2 and are therefore expected to result in linkage of cargos to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility. dynein | DYNC1H1 | neurological disease | cargo adaptor | processivity

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Section: Significancesupporting

confidence: 71%

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

Hoang

Schlager

Carter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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“…3B) (Bolhy et al, 2011;Splinter et al, 2010). Dynein is specifically recruited during G2, just in time for the apical aspect of interkinetic nuclear migration (Baffet et al, 2015). Occasionally, a nucleus does not complete nuclear migration to the apical surface before the onset of mitosis.…”

Section: Nuclear Migration In Developing Epitheliamentioning

confidence: 99%

Nuclear migration events throughout development

Bone

Starr

2016

Journal of Cell Science

110

113

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Moving the nucleus to a specific position within the cell is an important event during many cell and developmental processes. Several different molecular mechanisms exist to position nuclei in various cell types. In this Commentary, we review the recent progress made in elucidating mechanisms of nuclear migration in a variety of important developmental models. Genetic approaches to identify mutations that disrupt nuclear migration in yeast, filamentous fungi, Caenorhabditis elegans, Drosophila melanogaster and plants led to the identification of microtubule motors, as well as Sad1p, UNC-84 (SUN) domain and Klarsicht, ANC-1, Syne homology (KASH) domain proteins (LINC complex) that function to connect nuclei to the cytoskeleton. We focus on how these proteins and various mechanisms move nuclei during vertebrate development, including processes related to wound healing of fibroblasts, fertilization, developing myotubes and the developing central nervous system. We also describe how nuclear migration is involved in cells that migrate through constricted spaces. On the basis of these findings, it is becoming increasingly clear that defects in nuclear positioning are associated with human diseases, syndromes and disorders.

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“…CENP-F is sequestered in the nucleus in G2, but relocates, in a Cdk1-dependent way, to the NPCs in prophase (Baffet et a., 2015). Drug inhibition of G2-phase nuclear migration can be overcome by expression of BicD2 constitutively located to the NE by fusion to the nesprin-3 KASH domain.…”

Section: Cdk1 Controls Dynein/dynactin Recruitment To Npcsmentioning

confidence: 97%

“…This seems to be orchestrated by the G2/M phase cyclin dependent kinase, Cdk1 (Baffet et al, 2015). Inhibition of Cdk1 with drugs prevented nuclear migration and inhibited accumulation of dynein at the NE in G2.…”

Section: Cdk1 Controls Dynein/dynactin Recruitment To Npcsmentioning

confidence: 99%

Nuclear pore complex tethers to the cytoskeleton

Goldberg

2017

Seminars in Cell & Developmental Biology

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Cdk1 Activates Pre-mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem Cells

Cited by 93 publications

References 58 publications

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

Nuclear migration events throughout development

Nuclear pore complex tethers to the cytoskeleton

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