Nestin negatively regulates postsynaptic differentiation of the neuromuscular synapse

Yang, Jiefei; Dominguez, Bertha; Winter, Fred de; Gould, Thomas W.; Eriksson, John E.; Lee, Kuo‐Fen

doi:10.1038/nn.2747

Cited by 45 publications

(73 citation statements)

References 48 publications

(54 reference statements)

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“…This is in line with the expectation from in vitro studies showing that nestin serves as a scaffold for Cdk5 and regulates its kinase activity (Sahlgren et al, 2006). A recent RNAi-based study (Yang et al, 2011) further supports our conclusion as knockdown of nestin via RNAi in myotubes resulted in significant decrease of p35 expression and Cdk5 activity. Further support for the notion that nestin acts via the Cdk5 pathway was obtained from the similarity between the phenotypes of Cdk5/agrin and nestin/agrin double knock-out animals.…”

Section: Discussionsupporting

confidence: 92%

“…Further support for the notion that nestin acts via the Cdk5 pathway was obtained from the similarity between the phenotypes of Cdk5/agrin and nestin/agrin double knock-out animals. In all cases [i.e., Cdk5 deficiency (Lin et al, 2005), nestin RNAi knockdown (Yang et al, 2011), and nestin deficiency (our study)], the AChR clusterdispersing phenotype was partially rescued in agrin mutants. Our genetic and others' biochemical data (Sahlgren et al, 2006;Yang et al, 2011) strongly suggest that nestin is an important regulator of Cdk5 kinase activity identified as a dispersing signal for AChR clusters.…”

Section: Discussionmentioning

confidence: 51%

“…In all cases [i.e., Cdk5 deficiency (Lin et al, 2005), nestin RNAi knockdown (Yang et al, 2011), and nestin deficiency (our study)], the AChR clusterdispersing phenotype was partially rescued in agrin mutants. Our genetic and others' biochemical data (Sahlgren et al, 2006;Yang et al, 2011) strongly suggest that nestin is an important regulator of Cdk5 kinase activity identified as a dispersing signal for AChR clusters. In summary, our data indicate that although nestin is highly expressed during CNS development and commonly used for detection of neural stem/progenitor cells, it is dispensable for formation of the CNS.…”

Section: Discussionmentioning

confidence: 51%

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Nestin Is Not Essential for Development of the CNS But Required for Dispersion of Acetylcholine Receptor Clusters at the Area of Neuromuscular Junctions

Mohseni¹,

Sung²,

Murphy³

et al. 2011

J. Neurosci.

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Nestin is expressed in many different progenitors during development including those of the CNS, heart, skeletal muscle, and kidney. The adult expression is mainly restricted to the subependymal zone and dentate gyrus of the brain, the neuromuscular junction, and renal podocytes. In addition, this intermediate filament protein has served as a marker of neural stem/progenitor cells for close to 20 years. Therefore it is surprising that its function in development and adult physiology is still poorly understood. Here we report that nestin deficiency is compatible with normal development of the CNS. The mutant mice, however, show impaired motor coordination. Furthermore, we found that the number of acetylcholine receptor clusters, the nerve length, and the endplate bandwidth are significantly increased in neuromuscular junction area of nestin-deficient mice. This is similar to the phenotype described for deficiency of cyclindependent kinase 5 (Cdk5), a candidate downstream affecter of nestin. Moreover, we demonstrate that nestin deficiency can rescue maintenance of acetylcholine receptor clusters in the absence of agrin, similar to Cdk5/agrin double knock-outs, suggesting that the observed nestin deficiency phenotype is the consequence of aberrant Cdk5 activity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 51%

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Nestin Is Not Essential for Development of the CNS But Required for Dispersion of Acetylcholine Receptor Clusters at the Area of Neuromuscular Junctions

Mohseni¹,

Sung²,

Murphy³

et al. 2011

J. Neurosci.

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“…We hypothesised that nestin could affect FAK directly, in the same way that synemin, an intermediate filament protein that is structurally similar to nestin, binds to zyxin, thereby affecting its localisation at focal adhesions Sun et al, 2010). Nestin has been shown to have the propensity to act as a cytoskeletal signalling regulator, as it regulates Cdk5, with consequences for Cdk5 activation and localisation in neural progenitor cells, myoblasts and at the neuromuscular junctions (Mohseni et al, 2011;Pallari et al, 2011;Sahlgren et al, 2006;Yang et al, 2011). In agreement with these reports, our current results suggest that nestin also has the capacity to act as a cytoskeletal regulator of FAK organisation and activity.…”

Section: Discussionmentioning

confidence: 99%

Nestin regulates prostate cancer cell invasion by influencing FAK and integrin localisation and functions

Hyder

Lazaro

Pylvänäinen

et al. 2014

Journal of Cell Science

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BSTRACTNestin, an intermediate filament protein and marker of undifferentiated cells, is expressed in several cancers. Nestin is important for neuronal survival and is a regulator of myogenesis but its function in malignancy is ambiguous. We show that nestin downregulation leads to a redistribution of phosphorylated focal adhesion kinase (pFAK, also known as PTK2) to focal adhesions and alterations in focal adhesion turnover. Nestin downregulation also leads to an increase in the protein levels of integrin a5b1 at the cell membrane, activation of integrin b1 and an increase in integrin clustering. These effects have striking consequences for cell invasion, as nestin downregulation leads to a significant increase in pFAK-and integrin-dependent matrix degradation and cell invasion. Our results indicate that nestin regulates the localisation and functions of FAK and integrin. Because nestin has been shown to be prevalent in a number of specific cancers, our observations have broad ramifications for the roles of nestin in malignant transformation.

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“…Mutations in the lamins are associated with Emery-Dreifuss and Limb-girdle muscular dystrophy type 1B (60). Nestin (type VI) plays a role in the accumulation of acetylcholine receptors at the neuromuscular junction and in the development of myogenic cells (86,94). Muscles lacking keratin 19 (type I) or desmin (type III) are mildly myopathic and are weaker and more easily injured than wild-type (WT) (1,54,88).…”

mentioning

confidence: 99%

Myopathic changes in murine skeletal muscle lacking synemin

García‐Pelagio

Muriel

O’Neill

et al. 2015

American Journal of Physiology-Cell Physiology

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(IF) proteins are associated with defects in the organization of the contractile apparatus and its links to costameres, which connect the sarcomeres to the cell membrane. Here we study the role in skeletal muscle of synemin, a type IV IF protein, by examining mice null for synemin (synm-null). Synm-null mice have a mild skeletal muscle phenotype. Tibialis anterior (TA) muscles show a significant decrease in mean fiber diameter, a decrease in twitch and tetanic force, and an increase in susceptibility to injury caused by lengthening contractions. Organization of proteins associated with the contractile apparatus and costameres is not significantly altered in the synm-null. Elastimetry of the sarcolemma and associated contractile apparatus in extensor digitorum longus myofibers reveals a reduction in tension consistent with an increase in sarcolemmal deformability. Although fatigue after repeated isometric contractions is more marked in TA muscles of synm-null mice, the ability of the mice to run uphill on a treadmill is similar to controls. Our results suggest that synemin contributes to linkage between costameres and the contractile apparatus and that the absence of synemin results in decreased fiber size and increased sarcolemmal deformability and susceptibility to injury. Thus synemin plays a moderate but distinct role in fast twitch skeletal muscle. cytoskeleton; costameres; elastimetry; biomechanical properties; desmin A LARGE NUMBER OF HUMAN DISEASES, ranging from skin disorders (51), to premature aging (34, 64), to skeletal and cardiac myopathies (19,37), are linked to mutations in genes encoding intermediate filament (IF) proteins (25). Since the discovery of desmin, the major IF protein of striated muscle (49), its role and that of other IF proteins in muscle have been of keen interest to many laboratories (reviewed in 16). Our research on muscle IF proteins has addressed their role in force transmission and in organizing the sarcoplasm and stabilizing it against injury during force generation.Force generated in muscle can be transmitted radially, from the myofibrils, across the sarcolemma to the extracellular matrix and neighboring cells (11, 67). As a result, a significant amount of force is exerted on the sarcolemma and the structures that link it to the underlying contractile apparatus and the extracellular matrix. The ability of the sarcolemma with the underlying contractile apparatus to withstand the distortions caused during isotonic contractions (2, 11, 12) depends on specialized structures, termed "costameres" (66), that mediate the radial transmission of force across the sarcolemma (11). Costameres are structures at the sarcolemma of striated muscle fibers that align circumferentially around the Z disks and the M bands of the nearest myofibrils, and longitudinally, to form a rectilinear sarcolemmal network comprised of integral membrane proteins (such as dystroglycan, the sarcoglycans, and Na-K-ATPase), proteins of the extracellular matrix (such as laminin and collagen IV), and proteins of t...

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Nestin negatively regulates postsynaptic differentiation of the neuromuscular synapse

Cited by 45 publications

References 48 publications

Nestin Is Not Essential for Development of the CNS But Required for Dispersion of Acetylcholine Receptor Clusters at the Area of Neuromuscular Junctions

Nestin Is Not Essential for Development of the CNS But Required for Dispersion of Acetylcholine Receptor Clusters at the Area of Neuromuscular Junctions

Nestin regulates prostate cancer cell invasion by influencing FAK and integrin localisation and functions

Myopathic changes in murine skeletal muscle lacking synemin

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