Consequences of MEGF10 deficiency on myoblast function and Notch1 interactions

Saha, Madhurima; Mitsuhashi, Satomi; Jones, Michael D.; Manko, Kelsey; Reddy, Hemakumar M.; Bruels, Christine C.; Cho, Kyung Ah; Pacak, Christina A.; Draper, Isabelle; Kang, Peter B.

doi:10.1093/hmg/ddx189

Cited by 31 publications

(54 citation statements)

References 59 publications

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“…In skeletal muscle, Notch signalling regulates satellite cell self‐renewal and myoblast proliferation while inhibiting myoblast differentiation . Similar functions have been proposed for Megf10 in myoblasts . Further highlighting the parallels between Megf10/Drpr and Notch is the observation that developmental processes are sensitive to gene dosage in these proteins.…”

Section: Discussionmentioning

confidence: 56%

The impact of Megf10/Drpr gain‐of‐function on muscle development in Drosophila

et al. 2019

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Recessive mutations in multiple epidermal growth factor‐like domains 10 (MEGF10) underlie a rare congenital muscle disease known as MEGF10 myopathy. MEGF10 and its Drosophila homolog Draper (Drpr) are transmembrane receptors expressed in muscle and glia. Drpr deficiency is known to result in muscle abnormalities in flies. In the current study, flies that ubiquitously overexpress Drpr, or mouse Megf10, display developmental arrest. The phenotype is reproduced with overexpression in muscle, but not in other tissues, and with overexpression during intermediate stages of myogenesis, but not in myoblasts. We find that tubular muscle subtypes are particularly sensitive to Megf10/Drpr overexpression. Complementary genetic analyses show that Megf10/Drpr and Notch may interact to regulate myogenesis. Our findings provide a basis for investigating MEGF10 in muscle development using Drosophila.

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Section: Discussionmentioning

confidence: 56%

The impact of Megf10/Drpr gain‐of‐function on muscle development in Drosophila

et al. 2019

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“…MEGF10 induces clearance of apoptotic astrocytes in the brain [40] and its deficiency is associated with NOTCH signaling to regulate cell proliferation and migration [41, 42]. Furthermore, methylation of MEGF10 reduces relapse-free survival in neuroblastoma [43].…”

Section: Discussionmentioning

confidence: 99%

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

Hu¹,

Wang²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGFβ)/SMAD signaling pathway. Methods: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGFβ/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. Results: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGFβ/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. Conclusions: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGFβ/SMAD signaling-mediated EMT.

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“…In bone physiology, the von Willebrand factor C domain containing 2 gene (VWC2), a bone morphogenic protein, promotes bone formation, regeneration and healing 53,54 . In the context of Thoroughbred musculature, the multiple EGF like domains 10 gene (MEGF10) controls muscle cell proliferation and is involved in the regulation of myogenesis 55,56 and the collagen type VI alpha 3 chain gene (COL6A3) plays a major role in the maintenance of strength of muscle and connective tissue 57 . COL6A3 is one of three genes encoding components of collagen VI, which in the horse is expressed in developing cartilage 58 .…”

Section: Scientific Reports |mentioning

confidence: 99%

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

McGivney

Han

Corduff

et al. 2020

Sci Rep

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The Thoroughbred horse is a highly valued domestic animal population under strong selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of inbreeding in the population that may form the basis for evidence-based discussion amid concerns in the breeding industry over the increasing use of small numbers of popular sire lines, which may accelerate a loss of genetic diversity. In the most comprehensive globally representative sample of Thoroughbreds to-date (n = 10,118), including prominent stallions (n = 305) from the major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has been a highly significant decline in global genetic diversity during the last five decades (F iS R 2 = 0.942, P = 2.19 × 10 −13 ; F RoH R 2 = 0.88, P = 1.81 × 10 −10 ) that has likely been influenced by the use of popular sire lines. Estimates of effective population size in the global and regional populations indicate that there is some level of regional variation that may be exploited to improve global genetic diversity. Inbreeding is often a consequence of selection, which in managed animal populations tends to be driven by preferences for cultural, aesthetic or economically advantageous phenotypes. Using a composite selection signals approach, we show that centuries of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal growth and development, cellular stress and injury, metabolic pathways and neurotransmitters and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our results demonstrate that genomics-based approaches to identify genetic outcrosses will add valuable objectivity to augment traditional methods of stallion selection and that genomicsbased methods will be beneficial to actively monitor the population to address the marked inbreeding trend.The Thoroughbred is among the fastest animals selected by humans for sport, originating from "the commingled blood of Arabs, Turks and Barbs" 1 crossed with local British and Irish mares 2 "but selection and training have together made him a very different animal from his parent-stocks" 1 . The Thoroughbred is now a large (N ~ 500,000) global breed but, in the context of modern horse breeds, it has very low genetic diversity 3,4 due to the limited foundation alleles at the establishment of the stud book and restriction of external gene flow subsequent to the closing of the population 5-7 . In Thoroughbred horse breeding selection of potential champion racehorses is a global multi-billion-dollar business, but there is no systematic industry-mediated genomic selection or genetic population management. We hypothesised that the market-driven emphasis on highly valuable pedigrees and the common practice of inbreeding to successful ancestors in attempts to reinforce...

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Consequences of MEGF10 deficiency on myoblast function and Notch1 interactions

Cited by 31 publications

References 59 publications

The impact of Megf10/Drpr gain‐of‐function on muscle development in Drosophila

The impact of Megf10/Drpr gain‐of‐function on muscle development in Drosophila

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

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