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CRABP1-CaMKII-Agrnregulates the maintenance of neuromuscular junction in spinal motor neuron
- Source :
- Cell Death and Differentiation; 20220101, Issue: Preprints p1-13, 13p
- Publication Year :
- 2022
-
Abstract
- 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, Crabp1knockout (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 Agrnexpression and downstream muscle LRP4-MuSK signaling, thereby maintaining NMJ. A proof-of-concept was provided by specific re-expression of CRABP1 to rescue Agrnexpression and the phenotype. This study identifies CRABP1-CaMKII-Agrnsignaling 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.
Details
- Language :
- English
- ISSN :
- 13509047 and 14765403
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Cell Death and Differentiation
- Publication Type :
- Periodical
- Accession number :
- ejs59043945
- Full Text :
- https://doi.org/10.1038/s41418-022-00959-4