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

Haruka Munezane,Hiroaki Oizumi,Tomoko Wakabayashi,Shu Nishio,Tomoko Hirasawa,Takashi Sato,Akihiro Harada,Tomoyuki Yoshida,Takahiro Eguchi,Yuji Yamanashi,Tadafumi Hashimoto,Takeshi Iwatsubo

doi:10.1016/j.celrep.2019.11.112

Abstract

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. Invitro 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.

Highlights

In a search for neuronal receptors, we found that direct interaction of collagen XXV with type IIa receptor protein tyrosine phosphatases (RPTPs) PTPs and PTPd regulates the motor axon contact with the collagen-XXV-expressing target cells
Muscle-Derived Collagen XXV Is Necessary for Intramuscular Innervation To elucidate the physiological role of collagen XXV during development, we asked whether collagen XXV expressed in neurons or muscles contributes to intramuscular innervation by analyzing tissue-specific Col25a1 KO mice
The phrenic nerve in motor neuron-specific Col25a1 KO (MN-cKO) mice normally innervated the diaphragm at E13.5, followed by neuromuscular junction (NMJ) formation characterized by close apposition to the preformed acetylcholine receptor (AChR) clusters in the endplate area at E16.5 (Figure 1B)

Summary

Introduction

With regard to axon growth, studies on the NMJ showed that disruption of neuromuscular synaptic activity either by genetic deletion of the key molecules forming the NMJ, e.g., agrin, MuSK, and Dok-7, or by activityblocking agents resulted in abnormal extension of motor axons and prevented naturally occurring motor neuron death (Dahm and Landmesser, 1988; DeChiara et al, 1996; Gautam et al, 1996; Okada et al, 2006; Oppenheim et al, 2000; Terrado et al, 2001) These observations have predicted activity-dependent retrograde signaling that regulates intramuscular axon growth

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