Lineage context switches the function of aC. elegansPax6 homolog in determining a neuronal fate

Abstract

The sensory nervous system of C. elegans comprises cells with varied molecular and functional characteristics, and is, therefore, a powerful model for understanding mechanisms that generate neuronal diversity. We report here that VAB-3, a C. elegans homolog of the homeodomain-containing protein Pax6, has opposing functions in regulating expression of a specific chemosensory fate. A homeodomain-only short isoform of VAB-3 is expressed in BAG chemosensory neurons, where it promotes gene expression and cell function. In other cells, a long isoform of VAB-3, comprising a Paired homology domain and a homeodomain, represses expression of ETS-5, a transcription factor required for expression of BAG fate. Repression of ets-5 requires the Eyes Absent homolog EYA-1 and the Six-class homeodomain protein CEH-32. We determined sequences that mediate high-affinity binding of ETS-5, VAB-3 and CEH-32. The ets-5 locus is enriched for ETS-5-binding sites but lacks sequences that bind VAB-3 and CEH-32, suggesting that these factors do not directly repress ets-5 expression. We propose that a promoterselection system together with lineage-specific expression of accessory factors allows VAB-3/Pax6 to either promote or repress expression of specific cell fates in a context-dependent manner.This article has an associated 'The people behind the papers' interview.

Development of specialized sensory neurons engages a nuclear receptor required for functional plasticity

“…The cell fate determinant ETS-5 binds BAG-specific and pan-neuronal target genes To identify ETS-5 target genes, we immunoprecipitated ETS-5::GFP encoded by a transgene that rescues the ets-5 mutant phenotype (Brandt et al 2012) and sequenced bound chromatin. ETS-5 is expressed sparsely in the mature nervous system; consistent with a previous study (Brandt et al 2019), we detected ETS-5::GFP expression in 15 head neurons including BAG (Fig. 1A).…”

“…The most significantly enriched sequence motif proved a near-perfect match to a motif previously determined by in vitro studies of ETS-5 DNA-binding specificity (Fig. 1B; Brandt et al 2019). From three replicated chromatin immunoprecipitation/sequencing (ChIP-seq) experiments, we identified 1495 binding sites that were detected in each trial.…”

Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity

“…Site directed mutagenesis of predicted MADS, COUP-TF, MEIS and PAIRED BS leads to GFP expression defects, mainly in the PDE ( Figure 4A and Figure 4 - Figure supplement 1 ). VAB-3 protein contains two DNA binding domains, PAIRED and HD where each DNA domain fulfills specific functions (Brandt et al, 2019). Interestingly, we find that one of the two already identified functional HD BS matches a PAIRED-type HD consensus (HTAATTR, labeled as HD* in Figure 4 ) suggesting it could be recognized by VAB-3 and/or CEH-43.…”

“…The cat-2 minimal cis -regulatory module ( cat-2p21 ), in addition to the previously described ETS, PBX and HD BS (Flames and Hobert 2009; Doitsidou et al 2013) also contains predicted MADS, MEIS and PAIRED BS ( Figure 5B ). VAB-3 protein contains two DNA binding domains, PAIRED and HD where each DNA domain fulfills specific functions (Brandt et al 2019). Interestingly, we find that one of the two already identified functional HD BS matches a PAIRED-type HD consensus (HTAATTR, labeled as HD* in Figure 5 ) suggesting it could be recognized by VAB-3 and/or CEH-43.…”

Diet-responsive Transcriptional Regulation of Insulin in a Single Neuron Controls Systemic Metabolism

“…Here, we show that a conserved transcription factor, ETS-5, adaptively regulates an insulin-like peptide in response to a high-glucose diet. ETS-5 is an E-TwentySixdomain transcription factor, homologous to Pet1 in mammals, that is expressed in a specific set of glutamatergic neurons, including BAG and ASG (Brandt et al, 2019;Guillermin et al, 2011). The BAG neurons are well known for their gas-sensing functions -sensing down-steps in O 2 and acute CO 2 responses (Bretscher et al, 2008;Hallem and Sternberg, 2008;Zimmer et al, 2009).…”