Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho

Abstract

Apoptosis is essential for proper development and tissue homeostasis in metazoans. It plays a critical role in generating sexual dimorphism by eliminating structures that are not needed in a specific sex. The molecular mechanisms that regulate sexually dimorphic apoptosis are poorly understood. Here we report the identification of the ceh-30 gene as a key regulator of sex-specific apoptosis in Caenorhabditis elegans. Loss-of-function mutations in ceh-30 cause the ectopic death of male-specific CEM neurons. ceh-30 encodes a BarH homeodomain protein that acts downstream from the terminal sex determination gene tra-1, but upstream of, or in parallel to, the cell-death-initiating gene egl-1 to protect CEM neurons from undergoing apoptosis in males. The second intron of the ceh-30 gene contains two adjacent cis-elements that are binding sites for TRA-1A and a POU-type homeodomain protein UNC-86 and acts as a sensor to regulate proper specification of the CEM cell fate. Surprisingly, the N terminus of CEH-30 but not its homeodomain is critical for CEH-30's cell death inhibitory activity in CEMs and contains a conserved eh1/FIL domain that is important for the recruitment of the general transcriptional repressor UNC-37/Groucho. Our study suggests that ceh-30 defines a critical checkpoint that integrates the sex determination signal TRA-1 and the cell fate determination and survival signal UNC-86 to control the sex-specific activation of the cell death program in CEMs through the general transcription repressor UNC-37.[Keywords: C. elegans; apoptosis; sex-specific; unc-37/Groucho; ceh-30; transcriptional regulation] Supplemental material is available at http://www.genesdev.org.

Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans

“…The CB1490 males were not different from wild-type males in our bioassays. We used strain CU607 smIs23 [pkd-2::gfp+ pBX]; him-5(e1490) (43) to record responses from GFP-labeled CEM neurons. We crossed this smIs23 transgene into BC168 [unc-13(s69)] to obtain strain PS6327, used to record responses in the unc-13 synaptic mutant background.…”

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).…”

egl-1: a key activator of apoptotic cell death in C. elegans

“…We found that the CEMs did not inappropriately survive in these animals, indicating that the TRA-1 protein most probably promotes egl-1 transcription indirectly (P Grote and B Conradt; unpublished observation). Indeed, Bob Horvitz, Ding Xue et al have recently shown that TRA-1 acts through the BarH homeodomain transcription factor, CEH-30, to promote egl-1 transcription (Figure 3) (Peden et al, 2007;Schwartz and Horvitz, 2007). Specifically, the transcription of the ceh-30 gene, which was identified as a gene required for the survival of the CEMs in males, is directly repressed by TRA-1 in CEMs.…”