Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo

Gonçalves, João; Quintremil, Sebastián; Yi, Julie; Vallee, Richard B.

doi:10.1016/j.cub.2020.05.091

Cited by 42 publications

(71 citation statements)

References 61 publications

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“…The BICD2 protein mainly consists of coiled-coil (CC) segments 1, 2 and 3, each playing crucial roles in binding to other partners during various functions. The N-terminal CC1 segment binds to the dynein-dynactin complex, CC2 to kinesin KIF5A, and the C-terminal CC3 to several cargo proteins, such as RAB6A, RANBP2 [44], and the newly identified Nesprin-2 [15]. The truncation of the Cterminus in the CC3 domain thus appears to interfere with the ability of BICD2 to bind cargo proteins, as indicated in our results.…”

Section: Cellular Roles Of Dynein and Bicd2 In Brain Developmentsupporting

confidence: 60%

“…This truncated BicD2 mutant failed to localize at the nuclear envelop (NE), and hindered NE recruitment of the dynein complex. We also showed an interaction between Nesprin-2 and BicD2 [15], which was disrupted by the p.(Lys775Ter) variant. Remarkably, fusion of BicD2 K775X with a NE-localizing domain KASH rescued the neuronal migration defect in the developing mouse cortex.…”

Section: Introductionmentioning

confidence: 74%

“…Previous studies suggested that KASH-domain NE proteins Nesprin-1/2 may facilitate NE recruitment of the dynein complex [58]. Very recently, BicD2 has been shown to mediate dynein interaction to NE through its interaction with Nesprin-2 [15]. To examine whether BicD2 K775 variant could impair Nesprin-2dynein interaction, we used GST pulldown assay to check the interaction of the Nesprin-2 C-terminus with BicD2 WT and K775X.…”

Section: K775x Disrupted Interaction With Nesprin-2 and Ne Recruitmenmentioning

confidence: 99%

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Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Tsai

Cheng

Nian

et al. 2020

acta neuropathol commun

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During brain development, the nucleus of migrating neurons follows the centrosome and translocates into the leading process. Defects in these migratory events, which affect neuronal migration, cause lissencephaly and other neurodevelopmental disorders. However, the mechanism of nuclear translocation remains elusive. Using whole exome sequencing (WES), we identified a novel nonsense BICD2 variant p.(Lys775Ter) (K775X) from a lissencephaly patient. Interestingly, most BICD2 missense variants have been associated with human spinal muscular atrophy (SMA) without obvious brain malformations. By in utero electroporation, we showed that BicD2 knockdown in mouse embryos inhibited neuronal migration. Surprisingly, we observed severe blockage of neuronal migration in cells overexpressing K775X but not in those expressing wild-type BicD2 or SMA-associated missense variants. The centrosome of the mutant was, on average, positioned farther away from the nucleus, indicating a failure in nuclear translocation without affecting the centrosome movement. Furthermore, BicD2 localized at the nuclear envelope (NE) through its interaction with NE protein Nesprin-2. K775X variant disrupted this interaction and further interrupted the NE recruitment of BicD2 and dynein. Remarkably, fusion of BicD2-K775X with NE-localizing domain KASH resumed neuronal migration. Our results underscore impaired nuclear translocation during neuronal migration as an important pathomechanism of lissencephaly.

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Section: Cellular Roles Of Dynein and Bicd2 In Brain Developmentsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 74%

Section: K775x Disrupted Interaction With Nesprin-2 and Ne Recruitmenmentioning

confidence: 99%

See 1 more Smart Citation

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Tsai

Cheng

Nian

et al. 2020

acta neuropathol commun

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“…Similar findings suggest the Nesprin-1 or -2 CH domains are also dispensable for the development of mouse skeletal muscles and the epidermis ( Lüke et al, 2008 ; Stroud et al, 2017 ). Moreover, the CH domains are not required for Nesprin-2 mediated neuronal migration in the developing rat brain ( Gonçalves et al, 2020 ). Thus, the significance of the conserved CH domain is not clear.…”

Section: Discussionmentioning

confidence: 99%

The Nesprin-1/-2 ortholog ANC-1 regulates organelle positioning in C. elegans independently from its KASH or actin-binding domains

Hao

Kalra

Jameson

et al. 2021

eLife

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KASH proteins in the outer nuclear membrane comprise the cytoplasmic half of LINC complexes that connect nuclei to the cytoskeleton. Caenorhabditis elegans ANC-1, an ortholog of Nesprin-1/2, contains actin-binding and KASH domains at opposite ends of a long spectrin-like region. Deletion of either the KASH or calponin homology (CH) domains does not completely disrupt nuclear positioning, suggesting neither KASH nor CH domains are essential. Deletions in the spectrin-like region of ANC-1 led to significant defects, but only recapitulated the null phenotype in combination with mutations in the trans-membrane span. In anc-1 mutants, the ER, mitochondria, and lipid droplets were unanchored, moving throughout the cytoplasm. The data presented here support a cytoplasmic integrity model where ANC-1 localizes to the ER membrane and extends into the cytoplasm to position nuclei, ER, mitochondria, and likely other organelles in place.

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“…Zhang et al, 2011;Yeh et al, 2012;Bielska et al, 2014;Scherer et al, 2014;J. Zhang et al, 2014;Hoogenraad & Akhmanova, 2016;Reck-Peterson et al, 2018;Celestino et al, 2019;Gonçalves et al, 2020). Importantly, several coiled-coils-containing cargo adapters, including the BicD family and the Hook family of proteins, activate the processive movement of mammalian dynein in the presence of dynactin (McKenney et al, 2014;Schlager et al, 2014;Olenick et al, 2016;.…”

Section: Introductionmentioning

confidence: 99%

Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain

Qiu

Zhang

Rotty

et al. 2021

Preprint

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Cytoplasmic dynein is activated by cargo adapters, dynactin, and LIS1. However, it is unclear whether there are additional regulations for coordinating cargo binding and dynein activation. Here we found that a dynein AAA4 arginine-finger mutation in Aspergillus nidulans bypasses the requirement of LIS1 for dynein activation driven by the early endosomal adapter HookA. As AAA4 arginine-finger is implicated in AAA3 ATP hydrolysis, we examined AAA3 mutants defective in ATP binding and hydrolysis respectively. Astonishingly, blocking AAA3 ATP hydrolysis allows dynein activation by dynactin without LIS1 or HookA. As a consequence, dynein accumulates at microtubule minus ends while early endosomes stay near the plus ends. Blocking AAA3 ATP binding abnormally stabilizes the dynein-LIS1 interaction, suggesting that ATP binding at AAA3 regulates the dynamic dynein-LIS1 interaction. Thus, the AAA3 ATPase cycle not only regulates the mechanochemical cycle of dynein but also regulates the dynein-LIS1 interaction and the coordination between dynein activation and cargo binding.

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Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo

Cited by 42 publications

References 61 publications

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

The Nesprin-1/-2 ortholog ANC-1 regulates organelle positioning in C. elegans independently from its KASH or actin-binding domains

Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain

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