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Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception

Hedgehog (Hh) signaling patterns embryonic tissues and contributes to homeostasis in adults. In Drosophila, Hh transport and signaling are thought to occur along a specialized class of actin-rich filopodia, termed cytonemes. Here, we report that Interference hedgehog (Ihog) not only forms a Hh recep...

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Autores principales: Yang, Shu, Zhang, Ya, Yang, Chuxuan, Wu, Xuefeng, El Oud, Sarah Maria, Chen, Rongfang, Cai, Xudong, Wu, Xufeng S, Lan, Ganhui, Zheng, Xiaoyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131103/
https://www.ncbi.nlm.nih.gov/pubmed/34003115
http://dx.doi.org/10.7554/eLife.65770
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author Yang, Shu
Zhang, Ya
Yang, Chuxuan
Wu, Xuefeng
El Oud, Sarah Maria
Chen, Rongfang
Cai, Xudong
Wu, Xufeng S
Lan, Ganhui
Zheng, Xiaoyan
author_facet Yang, Shu
Zhang, Ya
Yang, Chuxuan
Wu, Xuefeng
El Oud, Sarah Maria
Chen, Rongfang
Cai, Xudong
Wu, Xufeng S
Lan, Ganhui
Zheng, Xiaoyan
author_sort Yang, Shu
collection PubMed
description Hedgehog (Hh) signaling patterns embryonic tissues and contributes to homeostasis in adults. In Drosophila, Hh transport and signaling are thought to occur along a specialized class of actin-rich filopodia, termed cytonemes. Here, we report that Interference hedgehog (Ihog) not only forms a Hh receptor complex with Patched to mediate intracellular signaling, but Ihog also engages in trans-homophilic binding leading to cytoneme stabilization in a manner independent of its role as the Hh receptor. Both functions of Ihog (trans-homophilic binding for cytoneme stabilization and Hh binding for ligand sensing) involve a heparin-binding site on the first fibronectin repeat of the extracellular domain. Thus, the Ihog-Ihog interaction and the Hh-Ihog interaction cannot occur simultaneously for a single Ihog molecule. By combining experimental data and mathematical modeling, we determined that Hh-Ihog heterophilic interaction dominates and Hh can disrupt and displace Ihog molecules involved in trans-homophilic binding. Consequently, we proposed that the weaker Ihog-Ihog trans interaction promotes and stabilizes direct membrane contacts along cytonemes and that, as the cytoneme encounters secreted Hh ligands, the ligands trigger release of Ihog from trans Ihog-Ihog complex enabling transport or internalization of the Hh ligand-Ihog-Patched -receptor complex. Thus, the seemingly incompatible functions of Ihog in homophilic adhesion and ligand binding cooperate to assist Hh transport and reception along the cytonemes.
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spelling pubmed-81311032021-05-19 Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception Yang, Shu Zhang, Ya Yang, Chuxuan Wu, Xuefeng El Oud, Sarah Maria Chen, Rongfang Cai, Xudong Wu, Xufeng S Lan, Ganhui Zheng, Xiaoyan eLife Developmental Biology Hedgehog (Hh) signaling patterns embryonic tissues and contributes to homeostasis in adults. In Drosophila, Hh transport and signaling are thought to occur along a specialized class of actin-rich filopodia, termed cytonemes. Here, we report that Interference hedgehog (Ihog) not only forms a Hh receptor complex with Patched to mediate intracellular signaling, but Ihog also engages in trans-homophilic binding leading to cytoneme stabilization in a manner independent of its role as the Hh receptor. Both functions of Ihog (trans-homophilic binding for cytoneme stabilization and Hh binding for ligand sensing) involve a heparin-binding site on the first fibronectin repeat of the extracellular domain. Thus, the Ihog-Ihog interaction and the Hh-Ihog interaction cannot occur simultaneously for a single Ihog molecule. By combining experimental data and mathematical modeling, we determined that Hh-Ihog heterophilic interaction dominates and Hh can disrupt and displace Ihog molecules involved in trans-homophilic binding. Consequently, we proposed that the weaker Ihog-Ihog trans interaction promotes and stabilizes direct membrane contacts along cytonemes and that, as the cytoneme encounters secreted Hh ligands, the ligands trigger release of Ihog from trans Ihog-Ihog complex enabling transport or internalization of the Hh ligand-Ihog-Patched -receptor complex. Thus, the seemingly incompatible functions of Ihog in homophilic adhesion and ligand binding cooperate to assist Hh transport and reception along the cytonemes. eLife Sciences Publications, Ltd 2021-05-18 /pmc/articles/PMC8131103/ /pubmed/34003115 http://dx.doi.org/10.7554/eLife.65770 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Developmental Biology
Yang, Shu
Zhang, Ya
Yang, Chuxuan
Wu, Xuefeng
El Oud, Sarah Maria
Chen, Rongfang
Cai, Xudong
Wu, Xufeng S
Lan, Ganhui
Zheng, Xiaoyan
Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title_full Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title_fullStr Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title_full_unstemmed Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title_short Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception
title_sort competitive coordination of the dual roles of the hedgehog co-receptor in homophilic adhesion and signal reception
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131103/
https://www.ncbi.nlm.nih.gov/pubmed/34003115
http://dx.doi.org/10.7554/eLife.65770
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