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Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development.

ABSTRACT: BACKGROUND:MC1R, a G-protein coupled receptor with high affinity for alpha-melanocyte stimulating hormone (?MSH), modulates pigment production in melanocytes from many species and is associated with human melanoma risk. MC1R mutations affecting human skin and hair color also have pleiotropic effects on the immune response and analgesia. Variants affecting human pigmentation in utero alter the congenital phenotype of both oculocutaneous albinism and congenital melanocytic naevi, and have a possible effect on birthweight. METHODS AND RESULTS:By in situ hybridization, RT-PCR and immunohistochemistry, we show that MC1R is widely expressed during human, chick and mouse embryonic and fetal stages in many somatic tissues, particularly in the musculoskeletal and nervous systems, and conserved across evolution in these three amniotes. Its dynamic pattern differs from that of TUBB3, a gene overlapping the same locus in humans and encoding class III ?-tubulin. The ?MSH peptide and the transcript for its precursor, pro-opiomelanocortin (POMC), are similarly present in numerous extra-cutaneous tissues. MC1R genotyping of variants p.(V60M) and p.(R151C) was undertaken for 867 healthy children from the Avon Longitudinal Study of Parent and Children (ALSPAC) cohort, and birthweight modeled using multiple logistic regression analysis. A significant positive association initially found between R151C and birth weight, independent of known birth weight modifiers, was not reproduced when combined with data from an independent genome-wide association study of 6,459 additional members of the same cohort. CONCLUSIONS:These data clearly show a new and hitherto unsuspected role for MC1R in noncutaneous solid tissues before birth.

SUBMITTER: Thomas AC

PROVIDER: S-EPMC6446732 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development.

Thomas Anna C AC Heux Pauline P Santos Chloe C Arulvasan Wisenave W Solanky Nita N Carey Magalie E ME Gerrelli Dianne D Kinsler Veronica A VA Etchevers Heather C HC

Birth defects research 20180108 5

<h4>Background</h4>MC1R, a G-protein coupled receptor with high affinity for alpha-melanocyte stimulating hormone (αMSH), modulates pigment production in melanocytes from many species and is associated with human melanoma risk. MC1R mutations affecting human skin and hair color also have pleiotropic effects on the immune response and analgesia. Variants affecting human pigmentation in utero alter the congenital phenotype of both oculocutaneous albinism and congenital melanocytic naevi, and have ...[more]

PMID: 29316344

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Project description:BACKGROUND: Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process. CONCLUSIONS/SIGNIFICANCE: Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis.

Dataset Information

Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development.

Publications

Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development.

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