Härönen Heli, Zainul Zarin, Tu Hongmin, Naumenko Nikolay, Sormunen Raija, Miinalainen Ilkka, Shakirzyanova Anastasia, Oikarainen Tuomo, Abdullin Azat, Martin Paula, Santoleri Sabrina, Koistinaho Jari, Silman Israel, Giniatullin Rashid, Fox Michael A, Heikkinen Anne, Pihlajaniemi Taina
Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Hum Mol Genet. 2017 Jun 1;26(11):2076-2090. doi: 10.1093/hmg/ddx101.
Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength. Collagen XIII is particularly important for the preterminal integrity, and when absent, destabilization of the motor nerves results in muscle regeneration and in atrophy especially in the case of slow muscle fibers. Collagen XIII was found to affect synaptic integrity through binding the ColQ tail of acetylcholine esterase. Although collagen XIII is a muscle-bound transmembrane molecule, it also undergoes ectodomain shedding to become a synaptic basal lamina component. We investigated the two forms' roles by novel Col13a1tm/tm mice in which ectodomain shedding is impaired. While postsynaptic maturation, terminal branching and neurotransmission was exaggerated in the Col13a1tm/tm mice, the transmembrane form's presence sufficed to prevent defects in transsynaptic adhesion, Schwann cell invagination/retraction, vesicle accumulation and acetylcholine receptor clustering and acetylcholinesterase dispersion seen in the Col13a1-/- mice, pointing to the transmembrane form as the major conductor of collagen XIII effects. Altogether, collagen XIII secures postsynaptic, synaptic and presynaptic integrity, and it is required for gaining and maintaining normal size, complexity and functional capacity of the neuromuscular synapse.
跨膜和细胞外信号（其中之一是胶原蛋白 XIII）调节神经肌肉突触的形成和功能，缺乏这些信号会导致肌无力。我们发现，胶原蛋白 XIII 基因敲除小鼠的表型变化比人类患者的症状要轻，但 Col13a1-/- 小鼠概括了 19 型先天性肌无力综合征的主要肌肉表现，并可作为疾病模型。在缺乏胶原蛋白 XIII 的情况下，神经肌肉突触无法达到完整的大小、排列、复杂性和功能，导致肌肉力量下降。胶原蛋白 XIII 对终末前的完整性尤为重要，缺乏时，运动神经的不稳定会导致肌肉再生和萎缩，尤其是慢肌纤维的情况。研究发现，胶原蛋白 XIII 通过结合乙酰胆碱酯酶的 ColQ 尾部来影响突触完整性。尽管胶原蛋白 XIII 是一种与肌肉结合的跨膜分子，但它也会经历胞外域脱落，成为突触基底层的一个组成部分。我们通过新型的 Col13a1tm/tm 小鼠研究了这两种形式的作用，在这种小鼠中，胞外域脱落受到损害。虽然在 Col13a1tm/tm 小鼠中，突触后成熟、终末分支和神经传递都有所增强，但跨膜形式的存在足以防止 Col13a1-/- 小鼠中出现的跨突触黏附、施万细胞内陷/回缩、囊泡聚集以及乙酰胆碱受体聚集和乙酰胆碱酯酶扩散等缺陷，这表明跨膜形式是胶原蛋白 XIII 发挥作用的主要传导者。总之，胶原蛋白 XIII 确保了突触后、突触和突触前的完整性，是获得和维持神经肌肉突触正常大小、复杂性和功能能力所必需的。
