TRA-1/GLI controls the expression of the Hox gene lin-39 during C. elegans vulval development

Abstract

The vulva of the Caenorhabditis elegans hermaphrodite develops from a subset of six vulval precursor cells (VPCs) by the combined effect of the Ras, Wingless and Notch signaling cascades, and of three redundant synMuv (synthetic Multivulva) pathways grouped into classes A, B and C. Here we show that signaling via the GLI- (Glioma-associated protein) like transcription factor TRA-1, which is the terminal regulator of the C. elegans sex determination cascade, is a newly discovered pathway specifying vulval cell fates. We found that TRA-1 accumulates in, and regulates the fusion process of, cells (including the VPCs and hypodermal cells) involved in vulval patterning. TRA-1 also influenced the expression of the Hox gene lin-39, a central regulator of vulval development. Furthermore, inactivation of tra-1, which transforms animals with hermaphrodite-specific karyotype into males, promoted vulval induction in synMuv A, but not in synMuv B, mutant background. This implies that TRA-1 interacts with the class B synMuv genes, many of which are involved in chromatin-mediated transcriptional repression of cell proliferation. These results may help to understand how compromised GLI activity in humans leads to cancer. Together, we suggest that the GLI protein family involved in several key developmental processes in both invertebrates and vertebrates regulates somatic cell fates through influencing, at least in part, the expression of specific Hox genes.

LIN-39 and the EGFR/RAS/MAPK pathway regulateC. elegansvulval morphogenesis via the VAB-23 zinc finger protein

“…Using a functional LIN-39::GFP reporter (Szabo et al, 2009), we detected strongest binding to region II, which contains the HOX/PBX sites, whereas regions I and III showed weaker binding relative a probe in the 3ЈUTR used as internal reference (Fig. 7B,E) (see Materials and methods).…”

Patterning of sexually dimorphic neurogenesis in the Caenorhabditis elegans ventral cord by Hox and TALE homeodomain transcription factors

“…For example, in hermaphrodites, TRA-1 ensures survival of hermaphrodite-specific neurons (HSNs) by repressing transcription of egl-1 and ensures death of male-specific neurons (CEMs) by repressing the anti-apoptotic gene ceh-30 (Conradt and Horvitz, 1999;Peden et al, 2007;Schwartz and Horvitz, 2007). Outside of the nervous system, TRA-1 interacts with cell cycle regulators to mediate sex-specific asymmetric division in the gonad and has been reported to regulate fusion of vulval precursor cells by influencing expression of lin-39 (Tilmann and Kimble, 2005;Szab o et al, 2009). It is, therefore, likely that TRA-1's role in ventral cord neuron specification involves the repression of a male-specific program of development in the hermaphrodite ventral nerve cord.…”

Sex‐specific regulation of aging in Caenorhabditis elegans

“…In the ChIP‐seq analysis, 184 TRA‐1‐binding sites were identified, which are fewer than typical for site‐specific transcription factors. Indeed, several previously described TRA‐1 target genes such as egl‐1 , ceh‐30, and lin‐39 (Conradt & Horvitz, 1999; Schwartz & Horvitz, 2007; Szabó et al., 2009) remained unidentified by this ChIP‐seq analysis (Berkseth et al., 2013). However, we know that a direct evidence for the functionality of the TRA‐1‐binding site we determined in the daf‐16 locus would be the elimination of the binding site by CRISPR/Cas technology which would block the regulatory interaction between TRA‐1 and daf‐16d/f and a isoforms in vivo.…”

“…In other words, TRA‐1 strengthens the function of daf‐16 in aging control, explaining why hermaphrodites live significantly longer than males in populations containing both sexes. At first sight, these results were somewhat unexpected as TRA‐1 had previously been known as a transcriptional repressor rather than an activator (Berkseth et al., 2013; Chen & Ellis, 2000; Conradt & Horvitz, 1999; Hargitai et al., 2009; Mason et al., 2008; Schwartz & Horvitz, 2007; Szabó et al., 2009; Yi et al., 2000). In case of mammalian GLI proteins, however, both activation and inhibition functions were observed (Hui & Angers, 2011).…”

“…Somatic sexual fates in C. elegans are specified by the global sex‐determination pathway, the terminal effector of which is the transcription factor TRA‐1 (sexual transformer) that exists in two major isoforms, A and B (Zarkower & Hodgkin, 1992). TRA‐1 is orthologous to mammalian GLI (glioma‐associated) and Drosophila Ci (Cubitus interruptus) proteins and determines hermaphrodite features by repressing the expression of male‐specific genes (Berkseth, Ikegami, Arur, Lieb & Zarkower, 2013; Chen & Ellis, 2000; Conradt & Horvitz, 1999; Hargitai et al., 2009; Mason, Rabinowitz & Portman, 2008; Schwartz & Horvitz, 2007; Szabó et al., 2009; Yi, Ross & Zarkower, 2000). In males, TRA‐1 appears to play only a minor role (Schvarzstein & Spence, 2006).…”