Roles of Collagen XXV and Its Putative Receptors PTPσ/δ in Intramuscular Motor Innervation and Congenital Cranial Dysinnervation Disorder

• Published in: Cell reports (Cambridge) Vol. 29; no. 13; pp. 4362 - 4376.e6
• Main Authors: Munezane, Haruka, Oizumi, Hiroaki, Wakabayashi, Tomoko, Nishio, Shu, Hirasawa, Tomoko, Sato, Takashi, Harada, Akihiro, Yoshida, Tomoyuki, Eguchi, Takahiro, Yamanashi, Yuji, Hashimoto, Tadafumi, Iwatsubo, Takeshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2019; Elsevier
• Subjects: collagen; motor neuron; neuromuscular development; receptor protein tyrosine phosphatase; collagen; receptor protein tyrosine phosphatase; neuromuscular development; motor neuron
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.112

Intramuscular motor innervation is an essential process in neuromuscular development. Recently, mutations in COL25A1, encoding CLAC-P/collagen XXV, have been linked to the development of a congenital cranial dysinnervation disorder (CCDD). Yet the molecular mechanisms of intramuscular innervation and the etiology of CCDD related to COL25A1 have remained elusive. Here, we report that muscle-derived collagen XXV is indispensable for intramuscular innervation. In developing skeletal muscles, Col25a1 expression is tightly regulated by muscle excitation. In vitro and cell-based assays reveal a direct interaction between collagen XXV and receptor protein tyrosine phosphatases (PTPs) σ and δ. Motor explant assays show that expression of collagen XXV in target cells attracts motor axons, but this is inhibited by exogenous PTPσ/δ. CCDD mutations attenuate motor axon attraction by reducing collagen XXV-PTPσ/δ interaction. Overall, our study identifies PTPσ/δ as putative receptors for collagen XXV, implicating collagen XXV and PTPσ/δ in intramuscular innervation and a developmental ocular motor disorder. [Display omitted] •Muscle-derived collagen XXV is essential for motor innervation during development•Collagen XXV directly interacts with its putative receptors PTPσ and PTPδ•Collagen XXV on target cells induces motor axon contact•CCDD mutations in collagen XXV attenuate PTPσ/δ interaction and axon attraction Munezane et al. demonstrate essential roles of muscle-derived collagen XXV in motor axon attraction and intramuscular innervation during development. Collagen XXV interacts with motor axons through its putative receptors PTPσ/δ. Congenital cranial dysinnervation disorder-causing mutations in collagen XXV attenuate the interaction with PTPσ/δ and disrupt innervation by motor axons.