Chinmo prevents transformer alternative splicing to maintain male sex identity.
Chinmo prevents transformer alternative splicing to maintain male sex identity.
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DOI：
10.1371/journal.pgen.1007203
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发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Bach EA
中科院分区：
文献类型：
--
作者：
Grmai L;Hudry B;Miguel-Aliaga I;Bach EA
两性动物的繁殖依赖于配子的成功产生，配子由生殖系执行，并得到体细胞支持细胞的帮助。果蝇的体细胞性别认同是由DMRT1双性同源基因(Dsx)的性别特异性亚型决定的。雌性特异的性致死基因(SXL)导致转换因子(Tra)与雌性异构体Traf的选择性剪接。反过来，Traf交替地将dsx剪接到雌性异构体dsxF上。在睾丸的雄性体细胞(CySCs)中，转录抑制因子Chinmo的缺失会导致它们“女性化”，类似于卵巢中的女性体细胞。这种体细胞性别转变导致生殖系分化的崩溃和男性不育。我们证明这种女性化是通过转录和转录后调节TRAF来实现的。我们发现缺乏chinmo的CySCs上调了tra基因的表达，同时上调了反式剪接因子Virilizer(Vir)和女性致死因子(2)d(Fl(2)d)的转录。在缺乏chinmo的CySCs中，Traf剪接导致以雄性亚型DsxM为代价产生DsxF，并且Traf和DsxF都是CySC性别转化所必需的。令人惊讶的是，失去chinmo后的CySC女性化不需要SXL，但需要Vir和Fl(2)d。与此一致，我们表明Vir和Fl(2)d都是雌性体细胞性腺tra选择性剪接所必需的。我们的工作揭示了成年男性干细胞中tra转录调控的必要性，并强调了以前未观察到的体内TRAF产生的SXL非依赖机制。总之，Chinmo对性别决定等级的转录控制对于性别二态组织中的性别维持至关重要，对保持生育能力也是至关重要的。性二态的成人组织，如卵巢和睾丸，需要持续的针对性别的指导才能正常发挥功能。果蝇雌性体细胞性别认同的建立是由选择性剪接级联控制的，其中性致死(SXL)产生雌性特有的蛋白质TransformerF(Traf)。相比之下，雄性缺乏SXL，并经历默认剪接，从而阻止Traf的产生。由于Traf在男性中的表达会导致性别转化和组织功能受损，所以男性一定已经进化出了强大的防御女性化的机制。在这里，我们研究了单一因素Chinmo在保护睾丸中的男性身份中的作用：男性躯体干细胞中Chinmo的丢失导致它们获得女性身份。我们证明这种女性化是通过TRAF及其下游靶标的诱导而发生的。令人惊讶的是，在这些变性细胞中没有诱导出SXL。相反，另外两种可供选择的剪接因子Virilizer和女性致死(2)d富含chinmo突变的体细胞，是它们女性化所必需的。我们的工作表明，对女性偏向的选择性剪接因子的转录抑制可以防止体细胞性腺中的性别转化，并且Traf的产生可以独立于SXL发生。鉴于性维持在组织动态平衡中的重要性，这种保护机制可能存在于其他组织中。
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. Sexually dimorphic adult tissues, like ovaries and testes, require continuous sex-specific instruction for proper function. 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). By contrast, males lack Sxl and undergo default splicing, preventing TraF production. Since TraF expression in males causes sex transformation and impairs tissue function, males must have evolved robust protection against feminization. Here, we investigate the role of a single factor, Chinmo, in protecting male sex identity in the testis: loss of Chinmo in male somatic stem cells causes them to acquire female identity. We demonstrate that this feminization occurs through the induction of TraF and its downstream targets. Surprisingly, Sxl is not induced in these sex transformed cells. Instead, two other alternative splice factors, Virilizer and Female lethal (2)d, are enriched in chinmo-mutant somatic cells and are required for their feminization. Our work demonstrates that transcriptional repression of female-biased alternative splice factors prevents sex transformation in the somatic gonad and that traF production can occur independently of Sxl. Given the importance of sex maintenance in tissue homeostasis, such protective mechanisms may exist in other tissues.
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DOI：
10.1073/pnas.1319063110
发表时间：
2013-11-19
影响因子：
11.1
作者：
Evans, Daniel S.;Cline, Thomas W.
通讯作者：
Cline, Thomas W.
影响因子：
3.3
作者：
Cook MS;Cazin C;Amoyel M;Yamamoto S;Bach E;Nystul T
通讯作者：
Nystul T
DOI：
10.1007/s004380050292
发表时间：
1996-11-27
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
Granadino, B;Penalva, LOF;Sanchez, L
通讯作者：
Sanchez, L
果蝇体形性腺细胞子集中的性别特异性双触及表达。
影响因子：
--
作者：
Hempel, Leonie U.;Oliver, Brian
通讯作者：
Oliver, Brian
影响因子：
11.4
作者：
BURTIS, KC;COSCHIGANO, KT;WENSINK, PC
通讯作者：
WENSINK, PC