A conserved chronobiological complex timesC. elegansdevelopment

Abstract

The mammalian PAS-domain protein PERIOD (PER) and itsC. elegansorthologue LIN-42 were proposed to constitute an evolutionary link between two distinct, circadian and developmental, timing systems. However, while the function of PER in animal circadian clocks is well understood molecularly and mechanistically, this is not true for LIN-42's function in timing rhythmic development. Here, using targeted deletions, we find that the LIN-42 PAS domains are dispensable for the protein's function in timing molts. Instead, we observe arrhythmic molts upon deletion of a distinct sequence element, conserved with PER. We show that this element mediates stable binding to KIN-20, theC. elegansCK1δ/ϵ orthologue. We demonstrate that CK1δ phosphorylates LIN-42 and define two conserved helical motifs, CK1δ-binding domain A (CK1BD-A) and CK1BD-B, that have distinct roles in controlling CK1δ-binding and kinase activity. KIN-20 and the LIN-42 CK1BD are required for proper molting timing. These interactions mirror the central role of a stable circadian PER-CK1 complex in setting a robust ~24h period. Hence, our results establish LIN-42/PER - KIN-20/CK1δ/ϵ as a functionally conserved signaling module of two distinct chronobiological systems.

MLT-11 is a transient apical extracellular matrix component required for cuticle patterning and function

“…These data were reminiscent of our work on NHR-23 as depletion of this factor causes aberrant aECM formation over the seam cells and nhr-23 activity also was necessary in the seam cells for developmental progression [32]. nhr-23 and lin-42 both regulate the molting timer and the heterochronic pathway and these two timers need to be tightly coordinated [27][28][29][30][31]36]. Pharmacologic uncoupling through nicotinic agonists results in animal death through rupturing when animals molt before seam cell division is completed [60].…”

“…A poorly understood genetic oscillator is thought to coordinate the expression of cuticle components and processing enzymes [25,26]. The molting cycle must also be tightly linked to developmental progression with homologs of circadian rhythm proteins (LIN-42/PER, NHR-23/ROR) playing important roles in both the molting and developmental timers [27][28][29][30][31][32][33][34][35][36]. Study of NHR-23-regulated genes revealed an enrichment in predicted protease and protease inhibitors [32,33].…”