Kif5b controls the localization of myofibril components for their assembly and linkage to the myotendinous junctions

Wang, Zai; Chen, Ju; Wong, Wai Man; Li, Xiuling; Xue, Wenqian; Lin, Raozhou; Wang, Jing; Wang, Peigang; Tanner, Julian A.; Cheah, Kathryn S.E.; Wu, Wutian; Huang, Jian

doi:10.1242/dev.085969

Cited by 56 publications

(64 citation statements)

References 43 publications

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“…Depletion of Kif5B (to 31±5% of mock, mean±s.d., n=3) results in concomitant depletion of KLC1 and KLC2 (supplementary material Fig. S1), as previously noted in primary mouse myotubes generated from Kif5B conditional knockout mice (Wang et al, 2013a). Similarly, siRNA-mediated depletion of KLC (to 3±2% of mock, mean±s.d., n=3) also reduces levels of Kif5B, consistent with coordinate regulation of KHC and KLC expression levels.…”

Section: Recruitment Of Exogenous Kif5b To the Nuclear Envelope Rescusupporting

confidence: 82%

“…The nuclei in mature muscle fibers are anchored under the sarcolemma at the cell periphery, and positioned to maximize internuclear distances, thereby minimizing transport distances from nucleus to cytoplasm (Bruusgaard et al, 2003). Abnormal aggregation or mispositioning of nuclei noted in many muscle diseases (Mattioli et al, 2011;Romero, 2010) correlates with muscle weakness and dysfunction observed in model organisms (Metzger et al, 2012;Wang et al, 2013a), suggesting that normal nuclear positioning is required for proper muscle cell function.…”

Section: Introductionmentioning

confidence: 99%

“…Loss of either the plus-end-directed kinesin-1 motor or the minus-end-directed dynein motor leads to reduced rates of translocation and rotation, although the effects are more pronounced in myotubes depleted of kinesin-1 (Wilson and Holzbaur, 2012). Furthermore, loss of Kif5B causes dramatic aggregation of nuclei at the midline of the cell in cultured mouse myotubes (Metzger et al, 2012;Wilson and Holzbaur, 2012), and in vivo in fly and mouse muscles (Metzger et al, 2012;Wang et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

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Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Wilson

Holzbaur

2015

Journal of Cell Science

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During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin-1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-typespecific nuclear positioning during development.

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Section: Recruitment Of Exogenous Kif5b To the Nuclear Envelope Rescusupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Wilson

Holzbaur

2015

Journal of Cell Science

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“…5A). Genomic deletion of KIF5B has been reported to disrupt organization of the Golgi complex, actin-cytoskeleton, and lysosomes in KIF5B-null myoblasts (28,29). Therefore, we examined whether expression of dnKIF5 affected the Golgi complex, actin-cytoskeleton and lysosomes in differentiated L6 myotubes.…”

Section: Functional Kif5b Is Required For Formation Of Large Dysferlimentioning

confidence: 99%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

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Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystrophy 2B and Myoshi myopathy in humans. Dysferlin has been proposed as a critical regulator of vesicle-mediated membrane resealing in muscle fibers, and localizes to muscle fiber wounds following sarcolemma damage. Studies in fibroblasts and urchin eggs suggest that trafficking and fusion of intracellular vesicles with the plasma membrane during resealing requires the intracellular cytoskeleton. However, the contribution of dysferlin-containing vesicles to resealing in muscle and the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear. Here, we use live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular wounding in muscle cells and examine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding. Our data indicate that dysferlin-containing vesicles move along microtubules via the kinesin motor KIF5B in muscle cells. Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the formation of extremely large cytoplasmic vesicles, and this response depends on both microtubules and functional KIF5B. In non-muscle cell types, lysosomes are critical mediators of membrane resealing, and our data indicate that dysferlincontaining vesicles are capable of fusing with lysosomes following wounding which may contribute to formation of large wound sealing vesicles in muscle cells. Overall, our data provide mechanistic evidence that microtubulebased transport of dysferlin-containing vesicles may be critical for resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organelle fusion in response to wounding in muscle cells.

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“…As the most abundant kinesin motor, kinesin-1 plays a significant role in the intracellular transportation, and its functions have been studied in a variety of cells, such as neurons, pancreatic beta cells and skeletal muscle cells [15][16][17]. However, the roles of kinesin-1 in chondrocytes and cartilage development are still not clear.…”

Section: Introductionmentioning

confidence: 99%

Multimodal nonlinear optical microscopy reveals critical role of kinesin-1 in cartilage development

Xue

Duan

et al. 2017

Biomed. Opt. Express

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Abstract:We developed a multimodal nonlinear optical (NLO) microscope system by integrating stimulated Raman scattering (SRS), second harmonic generation (SHG) and twophoton excited fluorescence (TPEF) imaging. The system was used to study the morphological and biochemical characteristics of tibial cartilage in a kinesin-1 (Kif5b) knockout mouse model. The detailed structure of fibrillar collagen in the extracellular matrix of cartilage was visualized by the forward and backward SHG signals, while high resolution imaging of chondrocytes was achieved by capturing endogenous TPEF and SRS signals of the cells. The results demonstrate that collagen fibrils in the superficial surface of the articular cartilage decreased significantly in the absence of Kif5b. The distorted morphology along with accumulated intracellular collagen was observed in the Kif5b-deficient chondrocytes, indicating the critical roles of kinesin-1 in the chondrocyte morphogenesis and collagen secretion. The study shows that multimodal NLO imaging method is an effective approach to investigate early development of cartilage.

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Kif5b controls the localization of myofibril components for their assembly and linkage to the myotendinous junctions

Cited by 56 publications

References 43 publications

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

Multimodal nonlinear optical microscopy reveals critical role of kinesin-1 in cartilage development

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