Activation of the Melanocortin-4 receptor signaling by α-MSH stimulates nerve-dependent mouse digit regeneration
Tóm tắt
Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration. However, the expression and function of Mc4r in the mouse limb and digit has not been fully investigated. Our previous work showed that Mc4r−/− mice fail to regenerate the digit, but whether activation of MC4R signaling could rescue digit regeneration, or stimulate proximal digit regeneration is not clear. We analyzed the expression dynamics of Mc4r in the embryonic and postnatal mouse limb and digit using the Mc4r-gfp mice. We found that Mc4r-GFP is mainly expressed in the limb nerves, and in the limb muscles that are undergoing secondary myogenesis. Expression of Mc4r-GFP in the adult mouse digit is restricted to the nail matrix. We also examined the effect of α-MSH on mouse digit regeneration. We found that administration of α-MSH in the Mc4r+/− mice rescue the delayed regeneration of distal digit tip. α-MSH could rescue distal digit regeneration in denervated hindlimbs. In addition, α-MSH could stimulate regeneration of the proximally amputated digit, which is non-regenerative. Mc4r expression in the mouse limb and digit is closely related to nerve tissues, and α-MSH/MC4R signaling has a neurotrophic role in mouse digit tip regeneration.
Tài liệu tham khảo
Anderson EJ, Cakir I, Carrington SJ, Cone RD, Ghamari-Langroudi M, Gillyard T, Gimenez LE, Litt MJ. 60 YEARS OF POMC: regulation of feeding and energy homeostasis by alpha-MSH. J Mol Endocrinol. 2016;56(4):T157–74. https://doi.org/10.1530/JME-16-0014.
Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, Mcgovern RA, Kenny CD, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123(3):493–505. https://doi.org/10.1016/j.cell.2005.08.035.
Borgens RB. Mice regrow the tips of their foretoes. Science. 1982;217(4561):747–50. https://doi.org/10.1126/science.7100922.
Chen Y, Xu H, Lin G. Generation of iPSC-derived limb progenitor-like cells for stimulating phalange regeneration in the adult mouse. Cell Discovery. 2017;3(1):17046. https://doi.org/10.1038/celldisc.2017.46.
Douglas BS. Conservative management of guillotine amputation of the finger in children. Aust Paediatr J. 1972;8(2):86–9. https://doi.org/10.1111/j.1440-1754.1972.tb01793.x.
Farkas JE, Monaghan JR. A brief history of the study of nerve dependent regeneration. Neurogenesis (Austin). 2017;4(1):e1302216. https://doi.org/10.1080/23262133.2017.1302216.
Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, Delvalle J, Yamada T. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993;268(20):15174–9. https://doi.org/10.1016/S0021-9258(18)82452-8.
Gautron L, Elmquist JK, Williams KW. Neural control of energy balance: translating circuits to therapies. Cell. 2015;161(1):133–45. https://doi.org/10.1016/j.cell.2015.02.023.
Hurren B, Collins JJ, Duxson MJ, Deries M. First neuromuscular contact correlates with onset of primary Myogenesis in rat and mouse limb muscles. PLoS One. 2015;10(7):e0133811. https://doi.org/10.1371/journal.pone.0133811.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131–41. https://doi.org/10.1016/S0092-8674(00)81865-6.
Illingworth CM. Trapped fingers and amputated finger tips in children. J Pediatr Surg. 1974;9(6):853–8. https://doi.org/10.1016/S0022-3468(74)80220-4.
Krashes MJ, Lowell BB, Garfield AS. Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci. 2016;19(2):206–19. https://doi.org/10.1038/nn.4202.
Kumar A, Brockes JP. Nerve dependence in tissue, organ, and appendage regeneration. Trends Neurosci. 2012;35(11):691–9. https://doi.org/10.1016/j.tins.2012.08.003.
Lepsen EW, Zhang J, Hollensted M, Madsbad S, Hansen T, Holst JJ, Jørgensen NR, Holm JC, Torekov SS. Adults with pathogenic MC4R mutations have increased final height and thereby increased bone mass. J Bone Miner Metab. 2020;38(1):117–25.
Li L, J. Z, Xu Y, Kuang Z, Zhang C, Li N, Lin G, Zhang C. Pharmacological modulation of dual melanocortin-4 receptor signaling by melanocortin receptor accessory proteins in the tetrapod Xenopus laevis. J Cell Physiol. 2021;2021:1–14. https://doi.org/10.1002/jcp.30280.
Litt MJ, Okoye GD, Lark D, Cakir I, Moore C, Barber MC, Atkinson J, Fessel J, Moslehi J, Cone RD. Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy. Elife. 2017;6. https://doi.org/10.7554/eLife.28118.
Liu H, Kishi T, Roseberry AG, Cai X, Lee CE, Montez JM, Friedman JM, Elmquist JK. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci. 2003;23(18):7143–54. https://doi.org/10.1523/JNEUROSCI.23-18-07143.2003.
Lotta LA, Mokrosinski J, Mendes De Oliveira E, Li C, Sharp SJ, Luan J, Brouwers B, Ayinampudi V, Bowker N, Kerrison N, et al. Human gain-of-function MC4R variants show signaling Bias and protect against obesity. Cell. 2019;177(3):597–607 e599. https://doi.org/10.1016/j.cell.2019.03.044.
Martin P. Tissue patterning in the developing mouse limb. Int J Dev Biol. 1990;34(3):323–36.
Martinelli CE, Keogh JM, Greenfield JR, Henning E, Van Der Klaauw AA, Blackwood A, O'rahilly S, Roelfsema F, Camacho-Hubner C, Pijl H, et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab. 2011;96(1):E181–8. https://doi.org/10.1210/jc.2010-1369.
Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He ZY, Huang YR, Zong HH, Friedman RA, Barasch J, Lanzano P, Deng L, Leibel RL, Rubin M, Nickolas T, Chung W, Zeltser LM, Williams KW, Pessin JE, Kousteni S. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017;543(7645):385–90. https://doi.org/10.1038/nature21697.
Mountjoy KG, Jenny Wu CS, Dumont LM, Wild JM. Melanocortin-4 receptor messenger ribonucleic acid expression in rat cardiorespiratory, musculoskeletal, and integumentary systems. Endocrinology. 2003;144(12):5488–96. https://doi.org/10.1210/en.2003-0570.
Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994;8(10):1298–308.
Mountjoy KG, Wild JM. Melanocortin-4 receptor mRNA expression in the developing autonomic and central nervous systems. Brain Res Dev Brain Res. 1998;107(2):309–14. https://doi.org/10.1016/S0165-3806(98)00015-7.
Neufeld DA, Zhao W. Phalangeal regrowth in rodents: postamputational bone regrowth depends upon the level of amputation. Prog Clin Biol Res. 1993;383A:243–52.
Panaro BL, Tough IR, Engelstoft MS, Matthews RT, Digby GJ, Moller CL, Svendsen B, Gribble F, Reimann F, Holst JJ, et al. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab. 2014;20(6):1018–29. https://doi.org/10.1016/j.cmet.2014.10.004.
Plantinga LC, Verhaagen J, Edwards PM, Hali M, Brakkee JH, Gispen WH. Pharmacological evidence for the involvement of endogenous alpha-MSH-like peptides in peripheral nerve regeneration. Peptides. 1995;16(2):319–24. https://doi.org/10.1016/0196-9781(94)00179-0.
Rinkevich Y, Montoro DT, Muhonen E, Walmsley GG, Lo D, Hasegawa M, Januszyk M, Connolly AJ, Weissman IL, Longaker MT. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. Proc Natl Acad Sci U S A. 2014;111(27):9846–51. https://doi.org/10.1073/pnas.1410097111.
Seifert AW, Muneoka K. The blastema and epimorphic regeneration in mammals. Dev Biol. 2018;433(2):190–9. https://doi.org/10.1016/j.ydbio.2017.08.007.
Siljee JE, Unmehopa UA, Kalsbeek A, Swaab DF, Fliers E, Alkemade A. Melanocortin 4 receptor distribution in the human hypothalamus. Eur J Endocrinol. 2013;168(3):361–9. https://doi.org/10.1530/EJE-12-0750.
Simkin J, Han M, Yu L, Yan M, Muneoka K. The mouse digit tip: from wound healing to regeneration. Methods Mol Biol. 2013;1037:419–35.
Sternson SM, Eiselt AK. Three pillars for the neural control of appetite. Annu Rev Physiol. 2016;79:401–23.
Stocum DL. Nerves and proliferation of progenitor cells in limb regeneration. Dev Neurobiol. 2019;79(5):468–78. https://doi.org/10.1002/dneu.22643.
Storer MA, Miller FD. Cellular and molecular mechanisms that regulate mammalian digit tip regeneration. Open Biol. 2020;10(9):200194. https://doi.org/10.1098/rsob.200194.
Takeo M, Chou WC, Sun Q, Lee W, Rabbani P, Loomis C, Taketo MM, Ito M. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature. 2013;499(7457):228–32. https://doi.org/10.1038/nature12214.
Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20(2):113–4. https://doi.org/10.1038/2407.
Van Der Kraan M, Tatro JB, Entwistle ML, Brakkee JH, Burbach JP, Adan RA, Gispen WH. Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. Brain Res Mol Brain Res. 1999;63(2):276–86. https://doi.org/10.1016/S0169-328X(98)00291-5.
Xu M, Alwahsh SM, Ramadori G, Kollmar O, Slotta JE. Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration. J Surg Res. 2016;203(1):222–30. https://doi.org/10.1016/j.jss.2013.12.019.
Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20(2):111–2. https://doi.org/10.1038/2404.
Yeo GS, Heisler LK. Unraveling the brain regulation of appetite: lessons from genetics. Nat Neurosci. 2012;15(10):1343–9. https://doi.org/10.1038/nn.3211.
Zhang C, Forlano PM, Cone RD. AgRP and POMC neurons are hypophysiotropic and coordinately regulate multiple endocrine axes in a larval teleost. Cell Metab. 2012;15(2):256–64. https://doi.org/10.1016/j.cmet.2011.12.014.
Zhang M, Chen Y, Xu H, Yang L, Yuan F, Li L, Xu Y, Chen Y, Zhang C, Lin G. Melanocortin receptor 4 signaling regulates vertebrate limb regeneration. Dev Cell. 2018;46(4):397–409 e395. https://doi.org/10.1016/j.devcel.2018.07.021.
Zhao W, Neufeld DA. Bone regrowth in young mice stimulated by nail organ. J Exp Zool. 1995;271(2):155–9. https://doi.org/10.1002/jez.1402710212.
Zhao Y, Xin Y, Chu H. MC4R is involved in neuropathic pain by regulating JNK signaling pathway after chronic constriction injury. Front Neurosci. 2019;13:919. https://doi.org/10.3389/fnins.2019.00919.
Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM. Multiple melanocortin receptors are expressed in bone cells. Bone. 2005;36(5):820–31. https://doi.org/10.1016/j.bone.2005.01.020.