FIGLA, a Basic Helix-Loop-Helix Transcription Factor, Balances Sexually Dimorphic Gene Expression in Postnatal Oocytes

Abstract

Maintenance of sex-specific germ cells requires balanced activation and repression of genetic hierarchies to ensure gender-appropriate development in mammals. Figla (factor in the germ line, alpha) encodes a germ cell-specific basic helix-loop-helix transcription factor first identified as an activator of oocyte genes. In comparing the ovarian proteome of normal and Figla null newborn mice, 18 testis-specific or -enhanced proteins were identified that were more abundant in Figla null ovaries than in normal ovaries. Transgenic mice, ectopically expressing Figla in male germ cells, downregulated a subset of these genes and demonstrated age-related sterility associated with impaired meiosis and germ cell apoptosis. Testis-associated genes, including Tdrd1, Tdrd6, and Tdrd7, were suppressed in the transgenic males with a corresponding disruption of the sperm chromatoid body and mislocalization of MVH and MILI proteins, previously implicated in posttranscriptional processing of RNA. These data demonstrate that physiological expression of Figla plays a critical dual role in activation of oocyte-associated genes and repression of sperm-associated genes during normal postnatal oogenesis.Mouse gestation takes ϳ20 days, and at embryonic day 10.5 (E10.5) the bipotential mammalian gonad commits to becoming a testis or an ovary, depending on the presence of the male-specifying Y chromosome. Subsequent gender-specific genetic hierarchies modulate the transition of the undifferentiated gonad to an ovary or testis, which produces haploid gametes through the reductive divisions of meiosis (5). However, sexual fate is plastic among metazoans (e.g., flies, worms, and mice), and this reversible commitment indicates an ongoing need for genetic controls to maintain one sex with concomitant nonexpression of genes that support the opposite identity (21, 33). Recently, Foxl2, a forkhead transcription factor expressed in somatic cells, has been implicated in maintaining female gonad sexual identify in adult mice; its ablation in postnatal ovaries leads to sex reversal via upregulation of Sox9 in somatic tissue independent of oocytes (51). It seems likely that genetic hierarchies expressed within oocytes complement these somatic signals to maintain appropriate germ cell identity by activating oocyte-associated genes and repressing sperm-associated genes during postnatal oogenesis.Members of the basic helix-loop-helix (bHLH) family of transcription factors are key regulators of cell growth and differentiation that can either activate or repress transcription of target genes (19). Figla (factor in the germ line, alpha; official name, folliculogenesis-specific basic helix-loop-helix) encodes a germ cell-specific bHLH transcription factor that was initially identified by its ability to coordinate the expression of the oocyte-specific zona pellucida genes (28). Although Figla transcripts are first detected in oocytes at E14.5, few differences are observed between normal and null transcriptomes prior to birth (20), at which time null oocytes do...

Molecular Cloning and Expression Profile of Sex-Specific Genes, Figla and Dmrt1, in the Protogynous Hermaphroditic Fish, Halichoeres Poecilopterus

“…The ovaries of Figla null mice show high expression of testis-related genes (Hu et al, 2010). In addition, ectopic expression of Figla in germ cells of male mice downregulates testis-associated genes (Hu et al, 2010). These findings support the possibility that low Figla expression enables the sustained transcription of testis-specific genes to induce formation of testis during the sex change in H. poecilopterus.…”

“…Throughout the gonadal sex change in this wrasse, spermatogenesis occurs to form functional testes (Kobayashi and Suzuki, 1994;Miyake et al, 2012). The ovaries of Figla null mice show high expression of testis-related genes (Hu et al, 2010). In addition, ectopic expression of Figla in germ cells of male mice downregulates testis-associated genes (Hu et al, 2010).…”

Genome-wide 5-hydroxymethylcytosine modification pattern is a novel epigenetic feature of globozoospermia

“…For instance, (i) growth differentiation factor 9 (GDF9) is significantly associated with sperm quality traits, and is involved in the initiation or maintenance of spermatogenesis [15]; (ii) methylation patterns of the nuclear ribonucleoprotein polypeptide N (SNRPN) promoters are associated with changes in sperm motility and morphology, which could lead to male infertility [16]; (iii) membrane-associated guanylate kinase, WW and PDZ domain containing 2 (MAGI-2), which is known to localize at the tight junction of epithelial cells, plays an important part in sperm cell maturation [17]; (iv) FIGLA (factor in the germ line, alpha) encodes a germ cell-specific basic helix-loop-helix transcription factor, which has essential roles in the repression of sperm-associated genes during normal postnatal oogenesis [18]. …”

Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing

“…More recent experiments involving Figla null mouse lines and expression microarrays have displayed target genes, such as kit, Dppa3, Pou5f1, and some Nlrp family members further downstream (Joshi et al, 2007). It has also been shown that Figla inhibits male specific genes which have suggested dichotomic molecular functions during germ cell development (Hu et al, 2010). FIGLA is also expressed early in humans, showing a significant increase at the time of primordial follicle development (Bayne et al, 2004).…”