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CRABP1-CaMKII-Agrn regulates the maintenance of neuromuscular junction in spinal motor neuron.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2022 Sep; Vol. 29 (9), pp. 1744-1756. Date of Electronic Publication: 2022 Feb 25. - 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, 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.<br /> (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
- Subjects :
- Agrin metabolism
Animals
Mice
Mice, Knockout
Motor Neurons metabolism
Neuromuscular Junction metabolism
Neuromuscular Junction pathology
Receptors, Retinoic Acid metabolism
Amyotrophic Lateral Sclerosis pathology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 29
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 35217789
- Full Text :
- https://doi.org/10.1038/s41418-022-00959-4