CRABP1-CaMKII-Agrn regulates the maintenance of neuromuscular junction in spinal motor neuron

Yu Lung Lin, Jennifer Nhieu, Pei Yao Liu, Gengyun Le, Dong Jun Lee, Chin Wen Wei, Yi Wei Lin, Sang Hyun Oh, Dawn Lowe, Li Na Wei

研究成果: 雜誌貢獻文章同行評審

8 引文 斯高帕斯(Scopus)


Cellular retinoic acid-binding protein 1 (CRABP1) binds retinoic acid (RA) specifically in the cytoplasm with unclear functions. CRABP1 is highly and specifically expressed in spinal motor neurons (MNs). Clinical and pre-clinical data reveal a potential link between CRABP1 and MN diseases, including the amyotrophic lateral sclerosis (ALS). We established a sequenced MN-muscle co-differentiation system to engineer an in vitro functional 3D NMJ model for molecular studies and demonstrated that CRABP1 in MNs contributes to NMJ formation and maintenance. Consistently, Crabp1 knockout (CKO) mice exhibited an adult-onset ALS-like phenotype with progressively deteriorated NMJs, characterized with behavioral, EchoMRI, electrophysiological, histological, and immunohistochemical studies at 2–20-months old. Mechanistically, CRABP1 suppresses CaMKII activation to regulate neural Agrn expression and downstream muscle LRP4-MuSK signaling, thereby maintaining NMJ. A proof-of-concept was provided by specific re-expression of CRABP1 to rescue Agrn expression and the phenotype. This study identifies CRABP1-CaMKII-Agrn signaling as a physiological pre-synaptic regulator in the NMJ. This study also highlights a potential protective role of CRABP1 in the progression of NMJ deficits in MN diseases.
頁(從 - 到)1744-1756
期刊Cell Death and Differentiation
出版狀態已發佈 - 9月 2022

ASJC Scopus subject areas

  • 分子生物學
  • 細胞生物學


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