Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice

Puckelwartz, Megan J.; Kessler, Eric; Zhang, Yuan; Hodzic, Didier; Randles, K. Natalie; Morris, Glenn E.; Earley, Judy U.; Hadhazy, Michele; Holaska, James M.; Mewborn, Stephanie K.; Pytel, Peter; McNally, Elizabeth M.

doi:10.1093/hmg/ddn386

Cited by 175 publications

(201 citation statements)

References 34 publications

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“…This report is consistent with the finding that depletion of the nucleoplasmic alpha isoform of LAP2 causes cardiac dysfunction in mice [48]. Mutations and polymorphisms in SYNE1 and SYNE2 genes, which respectively encode the KASH domain proteins nesprin-1 and nesprin-2, have also been reported in patients with muscular dystrophy and cardiomyopathy; disruption of the orthologous genes in mice causes skeletal and cardiac myopathy [49][50][51][52]. A mutation in SYNE1 has also been linked to an autosomal recessive form of arthrogryposis multiplex congenita, a syndrome of congenital joint contractures that results from reduced fetal movement [53].…”

Section: Muscular Dystrophysupporting

confidence: 90%

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

Worman

Dauer

2014

Neurotherapeutics

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Mutations in genes encoding nuclear envelope proteins cause a wide range of inherited diseases, many of which are neurological. We review the genetic causes and what little is known about pathogenesis of these nuclear envelopathies that primarily affect striated muscle, peripheral nerve and the central nervous system. We conclude by providing examples of experimental therapeutic approaches to these rare but important neuromuscular diseases.

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Section: Muscular Dystrophysupporting

confidence: 90%

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

Worman

Dauer

2014

Neurotherapeutics

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“…KASH-SUN protein complexes also have been implicated in roles related to muscular dystrophies (9,39). The degenerative phenotype may be related to the defects in myonuclear anchorage, including nonsynaptic anchorage.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that KASH (Klarsicht/ANC-1/Syne homologue) domain-containing and SUN domain-containing proteins (KASH/SUN proteins) form a complex at the nuclear envelope (NE) for various cellular functions (3)(4)(5)(6). Whereas a mammalian KASH protein has been found to have a critical function in myonuclear anchorage (7)(8)(9), the roles of SUN proteins in this process remain unclear.…”

mentioning

confidence: 99%

SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice

Lei

Zhang

Ding

et al. 2009

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

222

236

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How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei are evenly distributed at the periphery of each cell, with 3-8 nuclei anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain-containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain-containing proteins (SUN proteins) have been shown to interact with KASH domain-containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice are unknown. Here we show that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or all 4 Sun1/2 wild-type alleles revealed a gene dosage effect on synaptic nuclear anchorage. The organization of nonsynaptic nuclei is disrupted in Sun1/2 doubleknockout (DKO) mice as well. We further show that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.KASH domain ͉ Nesprin ͉ neuromuscular junction ͉ nuclear envelope protein ͉ Syne-1 P roper nuclear positioning relative to the cell body is important for many cellular processes during animal development. Mammalian skeletal muscle fibers are giant syncytial cells, each containing more than 100 nuclei. Each muscle fiber contains a neuromuscular junction (NMJ) that starts to form at approximately embryonic day 14 (E14) in mice (1). Following a multistep process involving the function of the agrin-MuSK-rapsynAChR pathway, the motor nerve terminal and the postsynaptic membrane become highly differentiated, ensuring reliable terminal transmission. The nuclei in the muscle fibers are positioned in a nonrandom manner, with 3-8 nuclei (synaptic nuclei) clustered beneath each NMJ and other nuclei (nonsynaptic nuclei) distributed evenly along the cell membrane (1, 2). How synaptic and nonsynaptic nuclei properly position themselves within each muscle fiber and the consequences of disrupting the nuclear positioning are attractive problems to investigate. Recent studies have indicated that KASH (Klarsicht/ANC-1/Syne homologue) domain-containing and SUN domain-containing proteins (KASH/SUN proteins) form a complex at the nuclear envelope (NE) for various cellular functions (3-6). Whereas a mammalian KASH protein has been found to have a critical function in myonuclear anchorage (7-9), the roles of SUN proteins in this process remain unclear.The SUN domain was first defined as a domain of shared homology between Sad1 in Schizosaccharomyces pombe and UNC-84 in Caenorhabditis elegans (10). SUN proteins are conserved inner nuclear membrane proteins containing at least 1 transmembrane domain and a C-terminal SUN...

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“…AHR1b mutation did not affect AHRR induction ( Figure 5A, 2-way ANOVA, P ¼ .043, n ¼ 3). Spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), which encodes a nuclear envelope protein (Muchir and Worman, 2007;Puckelwartz et al, 2009), was induced 6.2-fold by TCDD in wildtype cells. While AHR1b mutation did not affect SYNE-1 mRNA following TCDD treatment, mutation of AHR1a diminished TCDD induction by 74% ( Figure 5B, 2-way ANOVA, P ¼ .0066, n ¼ 3).…”

Section: Target Gene Induction By Tcddmentioning

confidence: 99%

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

2016

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Gene duplication confers genetic redundancy that can facilitate subfunctionalization, the partitioning of ancestral functions between paralogs. We capitalize on a recent genome duplication in Xenopus laevis (African clawed frog) to interrogate possible functional differentiation between alloalleles of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds and plays a role in the physiology and development of the cardiovascular, hepatic, and immune systems in vertebrates. X. laevis has 2 AHR genes, AHR1a and AHR1b. To test the hypothesis that the encoded proteins exhibit different molecular functions, we used TALENs in XLK-WG cells, generating mutant lines lacking functional versions of each AHR and measuring the transcriptional responsiveness of several target genes to the toxic xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the candidate endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). Mutation of either AHR1a or AHR1b reduced TCDD induction of the canonical AHR target, Cytochrome P4501A6, by 75%, despite the much lower abundance of AHR1b in wild-type cells. More modestly induced target genes, encoding aryl hydrocarbon receptor repressor (AHRR), spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), and gap junction protein gamma 1 (GJC1), were regulated solely by AHR1a. AHR1b was responsible for CYP1A6 induction by FICZ, while AHR1a mediated FICZ induction of AHRR. We conclude that AHR1a and AHR1b have distinct transcriptional functions in response to specific agonists, even within a single cell type. Functional analysis of frog AHR paralogs advances the understanding of AHR evolution and as well as the use of frog models of developmental toxicology such as FETAX.

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Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice

Cited by 175 publications

References 34 publications

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

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