Melanocortin Receptor 4 Signaling Regulates Vertebrate Limb Regeneration

Mengshi Zhang; Youwei Chen; Hanqian Xu; Li Yang; Feng Yuan; Lei Li; Ying Xu; Ying Chen; Chao Zhang; Gufa Lin

doi:10.1016/j.devcel.2018.07.021

Melanocortin Receptor 4 Signaling Regulates Vertebrate Limb Regeneration

Mengshi Zhang, Youwei Chen, Hanqian Xu, Li Yang, Feng Yuan, Lei Li, Ying Xu, Ying Chen, Chao Zhang, Gufa Lin

Stem Cell Institute

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Zhang et al. describe a requirement for melanocortin receptor 4 (Mc4r) signaling in tadpole limb and mouse digit regeneration. They show that Mc4r signaling regulates energy homeostasis and ROS production in the regenerating limb. In addition, α-MSH/Mc4r signaling can substitute for the effect of innervation on limb regeneration.

Original language	English (US)
Pages (from-to)	397-409.e5
Journal	Developmental Cell
Volume	46
Issue number	4
DOIs	https://doi.org/10.1016/j.devcel.2018.07.021
State	Published - Aug 20 2018

Bibliographical note

Funding Information:
The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China (31571491, 31771608, 81570760, and 31771283), the Science and Technology Commission of Shanghai Municipality (15PJ1407200), the Ministry of Science and Technology of China (2017YFA0103900, 2017YFA0103902, 2016YFA0102200), and the National Institute of Child Health and Human Development NIH (R01HD084440).

Funding Information:
The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China ( 31571491 , 31771608 , 81570760 , and 31771283 ), the Science and Technology Commission of Shanghai Municipality ( 15PJ1407200 ), the Ministry of Science and Technology of China ( 2017YFA0103900 , 2017YFA0103902 , 2016YFA0102200 ), and the National Institute of Child Health and Human Development NIH ( R01HD084440 ).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Mc4r
POMC
ROS
Xenopus
digit regeneration
energy metabolism
limb regeneration
neurotrophic factor
α-MSH

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10.1016/j.devcel.2018.07.021

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107305

Cite this

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title = "Melanocortin Receptor 4 Signaling Regulates Vertebrate Limb Regeneration",

abstract = "Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Zhang et al. describe a requirement for melanocortin receptor 4 (Mc4r) signaling in tadpole limb and mouse digit regeneration. They show that Mc4r signaling regulates energy homeostasis and ROS production in the regenerating limb. In addition, α-MSH/Mc4r signaling can substitute for the effect of innervation on limb regeneration.",

keywords = "Mc4r, POMC, ROS, Xenopus, digit regeneration, energy metabolism, limb regeneration, neurotrophic factor, α-MSH",

author = "Mengshi Zhang and Youwei Chen and Hanqian Xu and Li Yang and Feng Yuan and Lei Li and Ying Xu and Ying Chen and Chao Zhang and Gufa Lin",

note = "Funding Information: The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China (31571491, 31771608, 81570760, and 31771283), the Science and Technology Commission of Shanghai Municipality (15PJ1407200), the Ministry of Science and Technology of China (2017YFA0103900, 2017YFA0103902, 2016YFA0102200), and the National Institute of Child Health and Human Development NIH (R01HD084440). Funding Information: The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China ( 31571491 , 31771608 , 81570760 , and 31771283 ), the Science and Technology Commission of Shanghai Municipality ( 15PJ1407200 ), the Ministry of Science and Technology of China ( 2017YFA0103900 , 2017YFA0103902 , 2016YFA0102200 ), and the National Institute of Child Health and Human Development NIH ( R01HD084440 ). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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AU - Li, Lei

AU - Xu, Ying

AU - Chen, Ying

AU - Zhang, Chao

AU - Lin, Gufa

N1 - Funding Information: The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China (31571491, 31771608, 81570760, and 31771283), the Science and Technology Commission of Shanghai Municipality (15PJ1407200), the Ministry of Science and Technology of China (2017YFA0103900, 2017YFA0103902, 2016YFA0102200), and the National Institute of Child Health and Human Development NIH (R01HD084440). Funding Information: The authors thank Dr. Jonathan Slack for critical reading of the manuscript. The authors are grateful to Dr. Huxing Cui for sharing the Mc4r-gfp transgenic mice with us. This work was supported by research grants from the National Natural Science Foundation of China ( 31571491 , 31771608 , 81570760 , and 31771283 ), the Science and Technology Commission of Shanghai Municipality ( 15PJ1407200 ), the Ministry of Science and Technology of China ( 2017YFA0103900 , 2017YFA0103902 , 2016YFA0102200 ), and the National Institute of Child Health and Human Development NIH ( R01HD084440 ). Publisher Copyright: © 2018 Elsevier Inc.

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N2 - Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Zhang et al. describe a requirement for melanocortin receptor 4 (Mc4r) signaling in tadpole limb and mouse digit regeneration. They show that Mc4r signaling regulates energy homeostasis and ROS production in the regenerating limb. In addition, α-MSH/Mc4r signaling can substitute for the effect of innervation on limb regeneration.

AB - Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Zhang et al. describe a requirement for melanocortin receptor 4 (Mc4r) signaling in tadpole limb and mouse digit regeneration. They show that Mc4r signaling regulates energy homeostasis and ROS production in the regenerating limb. In addition, α-MSH/Mc4r signaling can substitute for the effect of innervation on limb regeneration.

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KW - POMC

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Melanocortin Receptor 4 Signaling Regulates Vertebrate Limb Regeneration

Abstract

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Keywords

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