Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion

Ortal Kraft-Sheleg; Shelly Zaffryar-Eilot; Olga Genin; Wesal Yaseen; Sharon Soueid-Baumgarten; Ofra Kessler; Tatyana Smolkin; Gal Akiri; Gera Neufeld; Yuval Cinnamon; Peleg Hasson

doi:10.1016/j.devcel.2016.02.009

Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion

Ortal Kraft-Sheleg
, Shelly Zaffryar-Eilot
, Olga Genin
, Wesal Yaseen
, Sharon Soueid-Baumgarten
, Ofra Kessler
, Tatyana Smolkin
, Gal Akiri
, Gera Neufeld
, Yuval Cinnamon
, Peleg Hasson

Technion-Israel Institute of Technology
Agricultural Research Organization of Israel

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

51 Scopus citations

Abstract

For muscles to function, myofibers have to stretch and anchor at the myotendinous junction (MTJ), a region rich in extracellular matrix (ECM). Integrin signaling is required for MTJ formation, and mutations affecting the cascade lead to muscular dystrophies in mice and humans. Underlying mechanisms for integrin activation at the MTJ and ECM modifications regulating its signaling are unclear. We show that lysyl oxidase-like 3 (LoxL3) is a key regulator of integrin signaling that ensures localized control of the cascade. In LoxL3 mutants, myofibers anchor prematurely or overshoot to adjacent somites, and are loose and lack tension. We find that LoxL3 complexes with and directly oxidizes Fibronectin (FN), an ECM scaffold protein and integrin ligand enriched at the MTJ. We identify a mechanism whereby localized LoxL3 secretion from myofiber termini oxidizes FN, enabling enhanced integrin activation at the tips of myofibers and ensuring correct positioning and anchoring of myofibers along the MTJ.

Original language	English
Pages (from-to)	550-561
Number of pages	12
Journal	Developmental Cell
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2016.02.009
State	Published - 7 Mar 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Funding

We thank T. Schultheiss for critical reading of the manuscript, E. Bengal for helpful discussions, and A. Stanhill for P97 antibody. We are further grateful to Dr. E. Suss-Toby, Dr. M. Gurewitz, L. Yehiam, M. Holdengreber, and L. Liba from the BCF Bioimaging Center (Faculty of Medicine, Technion) for their assistance with imaging and image analysis and to members of the animal facility for excellent technical assistance. Service for the quality control and microinjection of embryonic stem cells was provided by the Genome Engineering Service of the Mary Lyon Center at MRC Harwell ( www.har.mrc.ac.uk ). P.H. was supported by grants from the Israeli Science Foundation (1072/13) and Rappaport Family Institute . G.N. was supported by a grant from the Rappaport Family Institute and by a grant from the Israel Cancer Research Fund . Y.C. was supported by a grant from the Israeli Science Foundation (1255/13).

Funders	Funder number
Israeli Science Foundation	1072/13
Rappaport Family Institute
Israel Cancer Research Fund	1255/13

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title = "Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion",

abstract = "For muscles to function, myofibers have to stretch and anchor at the myotendinous junction (MTJ), a region rich in extracellular matrix (ECM). Integrin signaling is required for MTJ formation, and mutations affecting the cascade lead to muscular dystrophies in mice and humans. Underlying mechanisms for integrin activation at the MTJ and ECM modifications regulating its signaling are unclear. We show that lysyl oxidase-like 3 (LoxL3) is a key regulator of integrin signaling that ensures localized control of the cascade. In LoxL3 mutants, myofibers anchor prematurely or overshoot to adjacent somites, and are loose and lack tension. We find that LoxL3 complexes with and directly oxidizes Fibronectin (FN), an ECM scaffold protein and integrin ligand enriched at the MTJ. We identify a mechanism whereby localized LoxL3 secretion from myofiber termini oxidizes FN, enabling enhanced integrin activation at the tips of myofibers and ensuring correct positioning and anchoring of myofibers along the MTJ.",

author = "Ortal Kraft-Sheleg and Shelly Zaffryar-Eilot and Olga Genin and Wesal Yaseen and Sharon Soueid-Baumgarten and Ofra Kessler and Tatyana Smolkin and Gal Akiri and Gera Neufeld and Yuval Cinnamon and Peleg Hasson",

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AU - Genin, Olga

AU - Yaseen, Wesal

AU - Soueid-Baumgarten, Sharon

AU - Kessler, Ofra

AU - Smolkin, Tatyana

AU - Akiri, Gal

AU - Neufeld, Gera

AU - Cinnamon, Yuval

AU - Hasson, Peleg

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AB - For muscles to function, myofibers have to stretch and anchor at the myotendinous junction (MTJ), a region rich in extracellular matrix (ECM). Integrin signaling is required for MTJ formation, and mutations affecting the cascade lead to muscular dystrophies in mice and humans. Underlying mechanisms for integrin activation at the MTJ and ECM modifications regulating its signaling are unclear. We show that lysyl oxidase-like 3 (LoxL3) is a key regulator of integrin signaling that ensures localized control of the cascade. In LoxL3 mutants, myofibers anchor prematurely or overshoot to adjacent somites, and are loose and lack tension. We find that LoxL3 complexes with and directly oxidizes Fibronectin (FN), an ECM scaffold protein and integrin ligand enriched at the MTJ. We identify a mechanism whereby localized LoxL3 secretion from myofiber termini oxidizes FN, enabling enhanced integrin activation at the tips of myofibers and ensuring correct positioning and anchoring of myofibers along the MTJ.

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Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion

Abstract

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