Developing epidermis acquires nutrients from the external milieu by mTOR-dependent macropinocytosis

Abstract

The vertebrate epidermis transitions from a simple bilayer to a complex, multilayered epithelium during development. Periderm, the outermost layer of the bilayered epidermis, is in direct contact with the external aquatic surrounding. While the barrier function of the epidermis is well established, the functional repertoire of the developing epidermis remains unclear. Using zebrafish, we uncover a function of the periderm in nutrient acquisition. Our findings reveal a developmentally regulated wave of macropinocytosis, which is further amplified by extracellular nutrients, leading to the formation of large endo-lysosomal compartments termed Stimulated Nutrient Activated Compartments (SNACs). We identify mTOR as a key integrator of developmental and nutrient-derived signals that modulate SNAC biogenesis. A global lipidomics analysis demonstrates that macropinocytosis-mediated uptake drives the production of metabolically relevant lipids and enhances animal survival when gut function is compromised. Our study identifies a hitherto unappreciated route of nutrient acquisition by the metabolically responsive developing epidermis. We propose that this mechanism fulfils a vital nutritional role, particularly during the transitional phase when maternally provided resources are depleting and the gut is not yet fully operational.