Regulation of the circadian clock inC. elegansby clock gene homologskin-20andlin-42

Abstract

Circadian rhythms are endogenous oscillations present in nearly all organisms from prokaryotes to humans, allowing them to adapt to cyclical environments close to 24 hours. Circadian rhythms are regulated by a central clock, which is based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation. In the nematodeCaenorhabditis elegans,periodandcasein kinase 1ε/δare conserved aslin-42andkin-20, respectively. Here we studied the involvement oflin-42andkin-20in circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations oflin-42andkin-20generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and seam cells, a population of epidermal stem cells inC. elegansthat undergo multiple divisions during development. Depletion of LIN-42 and KIN-20 specifically in neuronal cells after development was sufficient to lengthen the period of oscillatingsur-5expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

A conserved chronobiological complex timesC. elegansdevelopment

“…mouse PER2 at 1225 amino acids (Jeon et al , 1999). LIN-42 lacks a CRY-binding domain, consistent with a lack of CRY orthologue in C. elegans , and in its tandem PER-ARNT-SIM (PAS) domains, only PAS-B is well conserved, adopts a canonical fold, and mediates dimerization in a mode identical to mammalian PER (Lamberti et al , 2023; Migliori et al , 2023). Finally, two stretches of sequence, previously termed SYQ and LT according to their first amino acids (Tennessen et al , 2006), bear sequence homology to the two PER CK1BD subdomains, CK1BD-A and CK1BD-B, but their function has remained unexplored.…”

“…The weak phenotypes seen with our precise deletion are particularly striking when considering that the PAS domains, and specifically the highly conserved PAS-B domain, mediate LIN-42 dimerization (Lamberti et al , 2023) - a function that is important for PER activity in circadian rhythms (Zheng et al , 1999). Although it remains to be determined whether the PAS domains are necessary for LIN-42 dimerization in vivo , it seems possible that LIN-42’s molting timing function does not require dimerization.…”