The C. elegans CDK8 Mediator module regulates axon guidance decisions in the ventral nerve cord and during dorsal axon navigation

Abstract

Receptors expressed on the growth cone of outgrowing axons detect cues required for proper navigation. The pathway choices available to an axon are in part defined by the set of guidance receptors present on the growth cone. Regulated expression of receptors and genes controlling the localization and activity of receptors ensures that axons respond only to guidance cues relevant for reaching their targets. In genetic screens for axon guidance mutants, we isolated an allele of let-19/mdt-13, a component of the Mediator, a large ~30 subunit protein complex essential for gene transcription by RNA polymerase II. LET-19/MDT-13 is part of the CDK8 module of the Mediator. By testing other Mediator components, we found that all subunits of the CDK8 module as well as some other Mediator components are required for specific axon navigation decisions in a subset of neurons. Expression profiling demonstrated that let-19/mdt-13 regulates the expression of a large number of genes in interneurons. A mutation in the sax-3 gene, encoding a receptor for the repulsive guidance cue SLT-1, suppresses the commissure navigation defects found in cdk-8 mutants. This suggests that the CDK8 module specifically represses the SAX-3/ROBO pathway to ensure proper commissure navigation.

Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis

“…This might not have been predicted, as the Cdk8 knockout mouse dies before implantation, with fragmented blastomeres at embryonic day 2.5 [14]. In worms and flies, Cdk8 mutants also display developmental defects [13,58]. Collectively, these data suggest that CDK8 requirements during development are context-specific and that future studies, beyond the scope of this paper, are needed to uncover these inputs.…”

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

“…Wild type was Bristol N2. cdk-8(tm1238) and cic-1(tm3740) are likely null alleles that abolish cdk-8 expression ( Figure S1B) and cic-1 function, respectively (see also Steimel et al 2013). For allele details, see www.wormbase.org.…”

cdc-25.4, aCaenorhabditis elegansOrtholog ofcdc25, Is Required for Male Mating Behavior

“…Interestingly, C. elegans CDK-5 is also required for neuronal functions (Ou et al 2010; Park et al 2011; Goodwin et al 2012; Monteiro et al 2012). Further, C. elegans CDK-8 regulates axon navigation decisions in the nervous system (Steimel et al 2013). These studies support the idea that functions of cell cycle regulators are not limited to the cell cycle regulation.…”

“…CDK-5 is also required for synapse elimination and formation (Park et al 2011), and for trafficking of glutamate receptors in the ventral nerve cord (Monteiro et al 2012). CDK-8 is required for axon navigation decisions in neurons (Steimel et al 2013), and also functions in vulval development by regulating the epidermal growth factor receptor-Ras-extracellular signal-regulated kinase pathway (Grants et al 2016). Taken together, these results suggest that CDKs phosphorylate not only cell cycle regulators, but also other regulators that are involved in diverse, important biological processes.…”