<i>Sex-lethal</i>
            enables germline stem cell differentiation by down-regulating Nanos protein levels during
            <i>Drosophila</i>
            oogenesis

Chau, Johnnie; Kulnane, Laura Shapiro; Salz, Helen K.

doi:10.1073/pnas.1120473109

Cited by 73 publications

(102 citation statements)

References 45 publications

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“…Bam is necessary and sufficient for GSC differentiation (McKearin and Ohlstein, 1995;McKearin and Spradling, 1990;Ohlstein and McKearin, 1997). Mechanistically, Bam is recruited to its target mRNAs through direct binding or its RNA-binding partners, such as Bgcn and Sxl, to repress target mRNA translation (Chau et al, 2009(Chau et al, , 2012Li et al, 2009Li et al, , 2013. Bam works with Smurf to repress BMP signaling in GSC progeny by unknown mechanisms (Casanueva and Ferguson, 2004).…”

Section: Introductionmentioning

confidence: 99%

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

Han

Song

et al. 2016

Development

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Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. However, it remains largely unknown how DNA damage affects both stem cell selfrenewal and differentiation. In this study, we show that DNA damage retards germline stem cell (GSC) self-renewal and progeny differentiation in a Lok kinase-dependent manner in the Drosophila ovary. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and a GSC progeny differentiation defect. Surprisingly, the elimination of Lok or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. In addition, the reduction in bone morphogenetic protein signaling and Shotgun expression only makes a limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a Lok-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that Lok kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation.

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Section: Introductionmentioning

confidence: 99%

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

Han

Song

et al. 2016

Development

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“…Cell-intrinsic programs, such as those carried out by the translational repressor Nanos, are also required for stem cell maintenance (Forbes and Lehmann, 1998;Gilboa and Lehmann, 2004;Harris et al, 2011;Wang and Lin, 2004). Following an oriented cell division, the GSC daughter that is specified as a CB displays an increase in Bam protein levels and a decrease in self-renewal factors, including Nanos protein (Chau et al, 2009(Chau et al, , 2012Li et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…We recently found that the switch to the CB fate requires the female-specific RNA-binding protein Sex lethal (Sxl) (Chau et al, 2009(Chau et al, , 2012. Germ cells without Sxl protein form tumors that comprise a few bona fide GSCs located at the tip of the germarium and cells that coexpress both Bam protein and a set of GSC markers, including Nanos protein.…”

Section: Introductionmentioning

confidence: 99%

“…Studies, showing that nanos is an Sxl target gene and that Nanos downregulation in CB cells is controlled at the level of translation, indicate that Sxl enables the GSC-to-CB switch by directly inhibiting nanos translation (Chau et al, 2009(Chau et al, , 2012Li et al, 2009). Although nanos is clearly necessary for tumor growth, both loss-and gain-of-function studies indicate that the failure to regulate nanos is not a trigger for tumorigenesis (Chau et al, 2012;Harris et al, 2011;Li et al, 2009). Consequently, the mechanism driving tumor formation in the absence of Sxl protein remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Maintenance of Drosophila germline stem cell sexual identity in oogenesis and tumorigenesis

2015

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Adult stem cells maintain tissue homeostasis by balancing selfrenewal and differentiation. In Drosophila females, germline stem cells (GSCs) require Sex lethal (Sxl) to exit the stem cell state and to enter the differentiation pathway. Without Sxl GSCs do not differentiate and instead form tumors. Previous studies have shown that these tumors are not caused by a failure in the self-renewal/ differentiation switch. Here, we show that Sxl is also necessary for the cell-autonomous maintenance of germ cell female identity and demonstrate that tumors are caused by the acquisition of male characteristics. Germ cells without Sxl protein exhibit a global derepression of testis genes, including Phf7, a male germline sexual identity gene. Phf7 is a key effector of the tumor-forming pathway, as it is both necessary and sufficient for tumor formation. In the absence of Sxl protein, inappropriate Phf7 expression drives tumor formation through a cell-autonomous mechanism that includes sex-inappropriate activation of Jak/Stat signaling. Remarkably, tumor formation requires a novel response to external signals emanating from the GSC niche, highlighting the importance of interactions between mutant cells and the surrounding normal cells that make up the tumor microenvironment. Derepression of testis genes, and inappropriate Phf7 expression, is also observed in germ cell tumors arising from the loss of bag of marbles (bam), demonstrating that maintenance of female sexual identity requires the concerted actions of Sxl and bam. Our work reveals that GSCs must maintain their sexual identity as they are reprogrammed into a differentiated cell, or risk tumorigenesis.

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“…The identity of Sxl target genes in the germ line is not well characterized; however, a recent study indicates that nanos, a gene required for GSC maintenance, is a Sxl target (7). Indeed, Sxl has been proposed to promote the differentiation of GSCs by downregulating Nanos levels in CBs by binding to the nanos 3′ UTR (7). In addition, Sxl is also important for repressing the expression of testis-specific genes, including Phf7, a male germline identity gene (8).…”

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confidence: 99%

spenito is required for sex determination in Drosophila melanogaster

Dong

Perrimon

2015

Proc. Natl. Acad. Sci. U.S.A.

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Sex-lethal (Sxl) encodes the master regulator of the sex determination pathway in Drosophila and acts by controlling sex identity in both soma and germ line. In females Sxl maintains its own expression by controlling the alternative splicing of its own mRNA. Here, we identify a novel sex determination gene, spenito (nito) that encodes a SPEN family protein. Loss of nito activity results in stem cell tumors in the female germ line as well as female-to-male somatic transformations. We show that Nito is a ubiquitous nuclear protein that controls the alternative splicing of the Sxl mRNA by interacting with Sxl protein and pre-mRNA, suggesting that it is directly involved in Sxl auto-regulation. Given that SPEN family proteins are frequently mutated in cancers, our results suggest that these factors might be implicated in tumorigenesis through splicing regulation.germ-line stem cell | sex determination | alternative splicing S ex determination in Drosophila is under the control of the master regulatory gene Sex-lethal (Sxl) (1). Sxl acts downstream of the X-chromosome counting mechanism and encodes a female-specific RNA binding protein. Once activated, Sxl maintains its own expression by regulating the alternative splicing of its pre-mRNA. Sxl controls female fate by controlling somatic and germ-line sex identity as well as dosage compensation (2). In female somatic cells, Sxl controls the alternative splicing of transformer (tra), which together with transformer2 (tra2) controls the alternative splicing of doublesex (dsx) and fruitless (fru). dsx and fru in turn encode sex-specific transcription factors that control male versus female morphology, physiology, and behavior (3, 4). In addition, Sxl represses the male-specific dosage compensation system by regulating male-specific lethal 2 (msl-2) both at the level of alternative splicing and translational control (5

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Sex-lethal enables germline stem cell differentiation by down-regulating Nanos protein levels during Drosophila oogenesis

Cited by 73 publications

References 45 publications

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

Maintenance of Drosophila germline stem cell sexual identity in oogenesis and tumorigenesis

spenito is required for sex determination in Drosophila melanogaster

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