Functional Genomic Identification of Genes Required for Male Gonadal Differentiation in <i>Caenorhabditis elegans</i>

Wnt signaling is tightly regulated during animal development and controls cell proliferation and differentiation. In C. elegans, activation of Wnt signaling alters the activity of the TCF/LEF transcription factor, POP-1, through activation of the Wnt/β-catenin or Wnt/β-catenin asymmetry pathways. In this study, we have identified CACN-1 as a potential regulator of POP-1 in C. elegans larval development. CACN-1/Cactin is a well-conserved protein of unknown molecular function previously implicated in the regulation of several developmental signaling pathways. Here we have used activation of POPTOP, a POP-1-responsive reporter construct, as a proxy for Wnt signaling. POPTOP requires POP-1 and SYS-1/β-catenin for activation in L4 uterine cells. RNAi depletion experiments show that CACN-1 is needed to prevent excessive activation of POPTOP and for proper levels and/or localization of POP-1. Surprisingly, high POPTOP expression correlates with increased levels of POP-1 in uterine nuclei, suggesting POPTOP may not mirror endogenous gene expression in all respects. Genetic interaction studies suggest that CACN-1 may act partially through LIT-1/NLK to alter POP-1 localization and POPTOP activation. Additionally, CACN-1 is required for proper proliferation of larval seam cells. Depletion of CACN-1 results in a loss of POP-1 asymmetry and reduction of terminal seam cell number, suggesting an adoption of the anterior, differentiated fate by the posterior daughter cells. These findings suggest CACN-1/Cactin modulates Wnt signaling during larval development.

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“…Our data are consistent with previous results [41] showing that POPTOP expression is dependent on POP-1 (P<0.0001, n = 16; Fig. 3A).…”

Section: Resultssupporting

confidence: 94%

CACN-1/Cactin Plays a Role in Wnt Signaling in C. elegans

et al. 2014

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“…RSPOs are expressed in vertebrates and invertebrates, such as hemichordates, chordates, and echinoderms, but screening of Drosophila melanogaster and Caenorhabditis elegans failed to identify any RSPO homolog (Yoon & Lee 2012). However, the WNT/b-catenin pathway is required for male cell fate commitment in the gonad of C. elegans (Kalis et al 2010). …”

Section: R105mentioning

confidence: 99%

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the b-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the b-catenin signaling pathway during ovarian differentiation in mice.Reproduction (2014) 148 R97-R110

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“…Other genes mediate subsequent sexual differentiation of the gonad, these include the forkhead transcription factor, fkh-6 (Chang et al, 2004), the cyclin D homolog cyd-1 (Tilmann and Kimble, 2005), and the Wnt pathway components sys-1, pop-1 , and lit-1 (Kalis et al, in press). Loss of each of these genes results in male gonads that are extensively feminized.…”

Section: Introductionmentioning

confidence: 99%

EGL-5/ABD-B plays an instructive role in male cell fate determination in the C. elegans somatic gonad

Kalis¹,

Murphy²,

Zarkower³

2010

Developmental Biology

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Hox genes of the Abdominal-B (Abd-B) class regulate gonadal development in diverse metazoans. Here we have investigated the role of the Abd-B homolog egl-5 in C. elegans gonadal development. Previous work showed that egl-5 is required male-specifically in the gonad and that mutant gonads are highly dysgenic and possibly feminized. We have used sex-specific gonadal reporter genes to confirm that the gonads of egl-5 males are extensively feminized. Sex-specific expression of egl-5 requires the global sex determination gene tra-1 and the gonadal masculinizing gene fkh-6, but mutagenesis of a short male gonadal enhancer element in egl-5 suggested that this regulation is indirect. Ectopic expression of EGL-5 in hermaphrodites is sufficient to induce male gonadal gene expression, indicating that EGL-5 plays an instructive role in male gonadal fate determination. EGL-5 acts in parallel with a Wnt/β -catenin pathway to regulate male gonadal fates and can physically interact with the Wnt pathway transcription factor POP-1 and modulate activity of a POP-1 dependent reporter gene. We propose that EGL-5 imparts sex-specific function on POP-1 by recruiting it to male-specific gonadal target genes.

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Functional Genomic Identification of Genes Required for Male Gonadal Differentiation in Caenorhabditis elegans

Cited by 30 publications

References 42 publications

CACN-1/Cactin Plays a Role in Wnt Signaling in C. elegans

CACN-1/Cactin Plays a Role in Wnt Signaling in C. elegans

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

EGL-5/ABD-B plays an instructive role in male cell fate determination in the C. elegans somatic gonad

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