Abstract
Reproduction in sexually dimorphic animals relies on successful gamete production, executed by the germline and aided by somatic support cells. Somatic sex identity in Drosophila is instructed by sex-specific isoforms of the DMRT1 ortholog Doublesex (Dsx). Female-specific expression of Sex-lethal (Sxl) causes alternative splicing of transformer (tra) to the female isoform traF. In turn, TraF alternatively splices dsx to the female isoform dsxF. Loss of the transcriptional repressor Chinmo in male somatic stem cells (CySCs) of the testis causes them to “feminize”, resembling female somatic stem cells in the ovary. This somatic sex transformation causes a collapse of germline differentiation and male infertility. We demonstrate this feminization occurs by transcriptional and post-transcriptional regulation of traF. We find that chinmo-deficient CySCs upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir) and Female lethal (2)d (Fl(2)d). traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation. Surprisingly, CySC feminization upon loss of chinmo does not require Sxl but does require Vir and Fl(2)d. Consistent with this, we show that both Vir and Fl(2)d are required for tra alternative splicing in the female somatic gonad. Our work reveals the need for transcriptional regulation of tra in adult male stem cells and highlights a previously unobserved Sxl-independent mechanism of traF production in vivo. In sum, transcriptional control of the sex determination hierarchy by Chinmo is critical for sex maintenance in sexually dimorphic tissues and is vital in the preservation of fertility.
Highlights
Sexual dimorphism, or the differences between male and female individuals in a species, is observed in many organisms, including insects, reptiles, and mammals
We find that chinmo-deficient cyst stem cells (CySCs) upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir) and Female lethal (2)d (Fl(2)d). traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation
Establishment of female somatic sex identity in Drosophila is controlled by an alternative splicing cascade wherein Sex-lethal (Sxl) produces the female-specific protein TransformerF (TraF)
Summary
The differences between male and female individuals in a species, is observed in many organisms, including insects, reptiles, and mammals. Differential gene expression via alternative splicing establishes the sex-specific differences observed in the fruit fly Drosophila melanogaster. In XX flies, a positive autoregulatory mechanism activates and maintains expression of the RNA-recognition motif (RRM) containing protein Sex-lethal (Sxl) [11]. Sxl binds directly to a polyuridine (poly(U)) tract upstream of exon 2 in transformer (tra) pre-mRNA [12, 13]. This results in the skipping of exon 2, which contains an early stop codon, and synthesis of full-length Tra (TraF) in females. All three proteins have an RRM and are required for sex-specific and non-sex-specific functions in Drosophila [14,15,16,17,18,19]
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