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 used Caenorhabditis elegans amphid sheath (AMsh) glia as a model and show that a conserved cis-Golgi membrane protein eas-1/GOLT1B negatively regulates glial growth. We found that eas-1 inhibits a conserved E3 ubiquitin ligase rnf-145/RNF145, which, in turn, promotes nuclear activation of sbp-1/ SREBP, a key regulator of sterol and fatty acid synthesis, to restrict cell growth. At early developmental stages, rnf-145 in the cis-Golgi network inhibits sbp-1 activation to promote the growth of glia, and when animals reach the adult stage, this inhibition is released through an eas-1-dependent shuttling of rnf-145 from the cis-Golgi to the trans-Golgi network to stop glial growth. Furthermore, we identified long-chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA), as downstream products of the eas-1-rnf-145-sbp-1 pathway that functions to prevent the overgrowth of glia. Together, our findings reveal a novel and potentially conserved mechanism underlying glial size control.
Highlights
A long-standing question in biology is how cells regulate their size [1,2,3]
To identify genes that may potentially regulate cell size, we conducted an unbiased forward genetic screen for mutants with abnormally sized amphid sheath (AMsh) cells and isolated a mutant yad70 with enlarged AMsh cells (Fig 1A and 1B). yad70 animals exhibited enlarged AMsh cells that increased in penetrance from larval stages to day 3 (D3) adults, where the phenotype penetrance reached 100% by the day 2 (D2) adult stage (Fig 1C)
Fig 1. eas-1 regulates the size of AMsh cells. (A) Schematic representation of an AMsh cell labeled in green. (B) Confocal images of AMsh cells from L1 and D3 adult stages in WT and eas-1(yad70) animals expressing Pf53f4.13::GFP
Summary
A long-standing question in biology is how cells regulate their size [1,2,3]. In unicellular organisms such as yeast, the extracellular nutritional environment plays a key role in controlling cell size, and this process is tightly coupled with cell proliferation [2,4,5]. Morphologically distinct glial cells grow and form close interactions with other cells [6,7,8].
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