Msx1 orchestrates retinal progenitor cell homeostasis from mechanical locking to synthetic arrest through the...

Despite the known association between the muscle segment homeobox 1 (Msx1) gene and neural diseases, its function in maintaining homeostasis in adult retinal progenitor cells (RPCs) unclear. We using an in vitro adult RPC model combined with short hairpin RNA-mediated knockdown, RNA sequencing, and tandem mass tag -based proteomics define Msx1 as a homeostatic rheostat that orchestrates cell structural dynamics and metabolic signaling pathways. We demonstrate that Msx1 loss triggers a mechanical locking state, defined by a paradoxical uncoupling of actomyosin dynamics: elevated Myh14 coexists with global attenuation of stability factors (Cnn1, Mad2l1b), causing aberrant punctate aggregation of Rho-GTPases and arresting cell movement, with subsequent metabolic paralysis through suppression PI3K/AKT signaling and induction of G2/M cell cycle arrest. Ultimately, these events converge toward synthetic arrest by the transcriptional translational decoupling of ribosomal protein large subunit hubs. These results indicate a severe blockade of de novo protein synthesis. Our findings indicate that Msx1 knockdown not only inhibit cell cycle progression but also disrupt the homeostatic rheostat, causing RPCs to undergo irreversible fate failure via a cascade of mechanical, metabolic, and synthetic failures. This regulatory model offers new insights into retinal regeneration, suggesting that therapeutic restoration of cytoskeletal and translational homeostasis may be required to re-establish the remodeling competence of retinal progenitor cells in degenerative retinal diseases.