CLAC-P/collagen type XXV is required for the intramuscular innervation of motoneurons during neuromuscular development.
Formation of proper neuromuscular connections is a process coordinated by both motoneuron-intrinsic and target-dependent programs. Under these programs, motoneurons innervate target muscles, escape programmed cell death during fetal development, and form neuromuscular junctions (NMJ). Although a number of studies have revealed molecules involved in axon guidance to target muscles and NMJ formation, little is known about the molecular mechanisms linking intramuscular innervation and target-derived trophic factor-dependent prevention of motoneuron apoptosis. Here we studied the physiological function of CLAC-P/collagen XXV, a transmembrane-type collagen originally identified as a component of senile plaque amyloid of Alzheimer's disease brains, by means of generating Col25a1-deficient (KO) mice. Col25a1 KO mice died immediately after birth of respiratory failure. In Col25a1 KO mice, motor axons projected properly toward the target muscles but failed to elongate and branch within the muscle, followed by degeneration of axons. Failure of muscular innervation in Col25a1 KO mice led to excessive apoptosis during development, resulting in almost complete and exclusive loss of spinal motoneurons and immaturity in skeletal muscle development. Bax deletion in Col25a1 KO mice rescued motoneurons from apoptosis, although motor axons remained halted around the muscle entry site. Furthermore, these motoneurons were positive for phosphorylated c-Jun, an indicator of insufficient supply of target-derived survival signals. Together, these observations indicate that CLAC-P/collagen XXV is a novel essential factor that regulates the initial phase of intramuscular motor innervation, which is required for subsequent target-dependent motoneuron survival and NMJ formation during development.
Department of Neuropathology & Neuroscience, Graduate School of Pharmaceutical Sciences, and Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8511, Japan, and Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Tomohiro
T
Tanaka
Tomoko
T
Wakabayashi
Hiroaki
H
Oizumi
Shu
S
Nishio
Takashi
T
Sato
Akihiro
A
Harada
Daisuke
D
Fujii
Yuko
Y
Matsuo
Tadafumi
T
Hashimoto
Takeshi
T
Iwatsubo
D000818:Animals; D003094:Collagen / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000294:innervation*; D055495:Neurogenesis / Q000502:physiology*; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003094:Collagen