Activation of the Melanocortin-4 receptor signaling by \u03b1-MSH stimulates nerve-dependent mouse digit regeneration

Hanqian Xu,Ying Chen,Hailin Zhang,Gufa Lin,Chao Zhang,Huiran Yang,Yanqing Fang

doi:10.1186/s13619-021-00081-9

Abstract

BackgroundExpression 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.ResultsWe 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.ConclusionsMc4r 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.

Highlights

Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration
We report that Mc4r is dynamically expressed in the mouse limb and digits, and confirm that α-MSH/melanocortin 4 receptor (MC4R) signaling has a neurotrophic role in mouse digit regeneration
To examine the dynamics of Mc4r expression during mouse limb development, we used the Mc4r-gfp transgenic mice, which faithfully reports the expression of Mc4r (Liu et al, 2003)

Summary

Introduction

Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration. Mc4r is expressed in the enteroendocrine L cells and its activation by α-MSH (α-melanocyte stimulating hormone) leads to the release of PYY (Peptide YY) and GLP-1 (Glucagon-like Protein 1), which regulates nutrients adsorption (Panaro et al, 2014). Mc4r is expressed in the rat hepatocyte and its expression level is elevated after partial hepatectomy (Xu et al, 2016). These studies indicate that MC4R has broader expression and functions in the peripheral organ and tissues, outside the central nervous system. The role of MC4R in those non-neural tissues and organs has not been adequately investigated

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