Dlk1 Is Necessary for Proper Skeletal Muscle Development and Regeneration

Waddell, Jolena N.; Zhang, Peijing; Wen, Yu; Gupta, Sanjay; Yevtodiyenko, Aleksey; Schmidt, Jennifer V.; Bidwell, Christopher A.; Kumar, Ashok; Kuang, Shihuan

doi:10.1371/journal.pone.0015055

Cited by 114 publications

(158 citation statements)

References 87 publications

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“…We have shown that Dlk1 expression peaks at day 7 following a knife-cut lesion in m. gastrocnemius (Andersen et al, 2009), yet the role of this high Dlk1 induction during muscle regeneration remains to be determined. In agreement with our previous results and those of others (Waddell et al, 2010), we found that DLK1 localizes mainly to interstitial cells (outside laminin + myofibers) ( Fig. 2A) of a nonmyogenic cell lineage (Andersen et al, 2009) (Fig.…”

Section: Dlk1-depleted Heterogeneous Muscle-derived Cell Cultures Exhsupporting

confidence: 93%

“…Likewise, diseased and regenerating muscle express high levels of Dlk1, though the number of DLK1 + satellite cells in these scenarios differ greatly, with only very few appearing during muscle regeneration of healthy muscle (Andersen et al, 2009). By contrast, numerous DLK1 + non-myogenic cells emerge in the interstitium between the myofibers upon muscle damage in human and mouse (Andersen et al, 2009;Waddell et al, 2010). Thus, as DLK1 can act in a cell autonomous or non-cell autonomous manner, it may affect myogenic precursor cells regardless of which type of cell expresses DLK1 in the muscle.…”

Section: Introductionmentioning

confidence: 99%

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Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration

et al. 2013

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SUMMARYMuscle development and regeneration is tightly orchestrated by a specific set of myogenic transcription factors. However, factors that regulate these essential myogenic inducers remain poorly described. Here, we show that delta-like 1 homolog (Dlk1), an imprinted gene best known for its ability to inhibit adipogenesis, is a crucial regulator of the myogenic program in skeletal muscle. Dlk1 −/− mice were developmentally retarded in their muscle mass and function owing to inhibition of the myogenic program during embryogenesis. Surprisingly however, Dlk1 depletion improves in vitro and in vivo adult skeletal muscle regeneration by substantial enhancement of the myogenic program and muscle function, possibly by means of an increased number of available myogenic precursor cells. By contrast, Dlk1 fails to alter the adipogenic commitment of muscle-derived progenitors in vitro, as well as intramuscular fat deposition during in vivo regeneration. Collectively, our results suggest a novel and surprising dual biological function of DLK1 as an enhancer of muscle development, but as an inhibitor of adult muscle regeneration.

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Section: Dlk1-depleted Heterogeneous Muscle-derived Cell Cultures Exhsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration

et al. 2013

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“…There is evidence showing that DLK1 may be involved in IGF1 signaling and in muscle growth through Akt phosphorylation (22,(31)(32)(33). We measured Akt phosphorylation in hypertrophic muscles.…”

Section: Significancementioning

confidence: 99%

“…If the point mutation occurs in both the paternal and maternal alleles, it causes no change in DLK1 protein expression (4), which is consistent with the mode of inheritance of the CLPG phenotype. It has been demonstrated that DLK1 protein expression is essential for determining muscle mass (20)(21)(22)(23)(24). Thus, a hypothesis predicting that maternal noncoding RNA might act as a negative regulator of DLK1 expression has been put forth; however, this hypothesis lacks evidence (25).…”

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confidence: 99%

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

Gao

Chen

Wang

et al. 2015

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

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Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance. muscle hypertrophy | callipyge | DLK1 | miR-379/miR-544 cluster T he callipyge (CLPG) phenotype can be characterized by an increase in muscle mass due to muscular hypertrophy and a unique non-Mendelian mode of inheritance (1-3). CLPG individuals are born with normal muscle histology and develop muscle hypertrophy at ∼1 mo of age. This hypertrophy occurs primarily in the muscles of the pelvic limbs and loin and some muscles in the shoulder, which are enriched with a high proportion of type IIB fast-twitch glycolytic fibers (4). Although the molecular regulation of these hypertrophic processes is yet to be determined, Delta-like 1 homolog (DLK1) is found to be the causative protein (5-10). The unique mode of inheritance of the CLPG phenotype has attracted a great deal of attention within the scientific community. The CLPG offspring inherit the phenotype only when the mutated allele comes from the father and the wild-type allele from the mother (CLPG PAT /+ MAT ). CLPG PAT /CLPG MAT offspring exhibit a wild-type phenotype, despite carrying a CLPG mutation on the paternal chromosome. This unusual mode of inheritance led to the development of the genetic concept of polar overdominance (2, 11).The CLPG mutation has been mapped to the Dlk1-Dio3 imprinted domain, which spans ∼1 Mb and harbors at least three protein-encoding genes, including Dlk1, Peg11/Rtl1, and Dio3, and multiple noncoding RNA genes, including Gtl2, anti-Peg11/anti-Rtl1, Meg8, Mirg, C/D small nucleolar RNAs (snoRNAs), and microRNA clusters [the microRNA (miR) 379 and miR-127 clusters] (12-14). The coding genes are expressed paternally, whereas the noncoding genes are expressed maternally (15,16). Further analysis revealed a point mutation (A to G transition) within the intergenic region between the Dlk1 and Gtl2 genes of the imprinted Dlk1-Dio3 region (17, 18), which affects a muscle-specific, long-range cis-acting ...

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“…However, loss of Dlk1 expression from the myogenic lineage causes a reduction in muscle mass by reducing myofibre number (Waddell et al 2010). Roles for Rtl1, Dio3 or the ncRNAs in muscle development have not been established, and thus the contribution of Dlk1-Dio3 cluster genes to control of myogenic development has yet to be elucidated.…”

Section: Musclementioning

confidence: 99%

Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models

Howard

Charalambous

2015

Reproduction

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Uniparental inheritance of chromosome 14q32 causes developmental failure during gestation and early postnatal development due to mis-expression of a cluster of imprinted genes under common epigenetic control. Two syndromes associated with chromosome 14q32 abnormalities have been described, Kagami-Ogata and Temple syndromes. Both of these syndromes are characterised by specific impairments of intrauterine development, placentation and early postnatal survival. Such abnormalities arise because the processes of intrauterine growth and postnatal adaptation are critically modulated by the dosage of imprinted genes in the chromosome 14q32 cluster. Much of our understanding of how the imprinted genes in this cluster are regulated, as well as their individual functions in the molecular pathways controlling growth and postnatal adaptation, has come from murine models. Mouse chromosome 12qF1 contains an imprinted region syntenic to human chromosome 14q32, collectively referred to as the Dlk1-Dio3 cluster. In this review, we will summarise the wealth of information derived from animal models of chromosome 12 imprinted gene mis-regulation, and explore the relationship between the functions of individual genes and the phenotypic result of their mis-expression. As there is often a considerable overlap between the functions of genes in the Dlk1-Dio3 cluster, we propose that the expression dosage of these genes is controlled by common regulatory mechanisms to co-ordinate the timing of growth and postnatal adaptation. While the diseases associated with mis-regulated chromosome 14 imprinting are rare, studies carried out in mice on the functions of the affected genes as well as their normal regulatory mechanisms have revealed new mechanistic pathways for the control of growth and survival in early life.Reproduction (2015) 149 R237-R249

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Dlk1 Is Necessary for Proper Skeletal Muscle Development and Regeneration

Cited by 114 publications

References 87 publications

Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration

Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models

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