A glycogenolytic switch preserves epithelial morphogenesis from proteotoxic disruption
July 3
A new study from investigators at the Institute for Developmental Dynamics has uncovered an unexpected guardian of tissue integrity during embryogenesis: glycogen turnover in epithelial progenitors. Published in Nature Cell Biology, the work demonstrates that mobilizing glycogen reserves within pattern-forming cells prevents toxic protein accumulation and the ensuing degenerative malformations.
Glycogen is conventionally viewed as a hepatic or myogenic energy depot. Although trace amounts are present in embryonic epithelia, its significance for morphogenesis has long been regarded as minimal. “These findings overturn that assumption in a dramatic way,” notes the senior investigator. “Stored glycogen is not passive; it actively intersects with developmental pathology.”
Using both Drosophila imaginal discs and human ectodermal organoids engineered to model proteotoxic dysmorphogenesis, the team discovered that epithelial cells accrue excessive glycogen during defective patterning. Crucially, this surplus exacerbates the phenotype. The lead author explains that a misfolded cytoskeletal scaffold protein—prone to forming intracellular fibrils—directly binds glycogen granules, immobilising them and suppressing glycogen phosphorylase–mediated breakdown. Blocking the interaction restored glycogenolysis, reduced aggregate burden, and rescued normal epithelial architecture, highlighting a therapeutically targetable sugar switch in developmental disease.