Regulation of glial size by eicosapentaenoic acid through a novel Golgi apparatus mechanism

Abstract

Coordination of cell growth is essential for the development of the brain, but the molecular mechanisms underlying the regulation of glial and neuronal size are poorly understood. To investigate the mechanisms involved in glial size regulation, we usedCaenorhabditis elegansamphid sheath (AMsh) glia as a model and show that a conservedcis-Golgi membrane proteineas-1/GOLT1Bnegatively regulates glial growth. We found thateas-1inhibits a conserved E3 ubiquitin ligasernf-145/RNF145, which, in turn, promotes nuclear activation ofsbp-1/SREBP, a key regulator of sterol and fatty acid synthesis, to restrict cell growth. At early developmental stages,rnf-145in thecis-Golgi network inhibitssbp-1activation to promote the growth of glia, and when animals reach the adult stage, this inhibition is released through aneas-1-dependent shuttling ofrnf-145from thecis-Golgi to thetrans-Golgi network to stop glial growth. Furthermore, we identified long-chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA), as downstream products of theeas-1-rnf-145-sbp-1pathway that functions to prevent the overgrowth of glia. Together, our findings reveal a novel and potentially conserved mechanism underlying glial size control.