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chinmo-mutant spermatogonial stem cells cause mitotic drive by evicting non-mutant neighbors from the niche

Tseng, Chen-Yuan; Burel, Michael; Cammer, Michael; Harsh, Sneh; Flaherty, Maria Sol; Baumgartner, Stefan; Bach, Erika A
Niches maintain a finite pool of stem cells via restricted space and short-range signals. Stem cells compete for limited niche resources, but the mechanisms regulating competition are poorly understood. Using the Drosophila testis model, we show that germline stem cells (GSCs) lacking the transcription factor Chinmo gain a competitive advantage for niche access. Surprisingly, chinmo-/- GSCs rely on a new mechanism of competition in which they secrete the extracellular matrix protein Perlecan to selectively evict non-mutant GSCs and then upregulate Perlecan-binding proteins to remain in the altered niche. Over time, the GSC pool can be entirely replaced with chinmo-/- cells. As a consequence, the mutant chinmo allele acts as a gene drive element; the majority of offspring inherit the allele despite the heterozygous genotype of the parent. Our results suggest that the influence of GSC competition may extend beyond individual stem cell niche dynamics to population-level allelic drift and evolution.
PMID: 34942115
ISSN: 1878-1551
CID: 5109062

Proliferative stem cells maintain quiescence of their niche by secreting the Activin inhibitor Follistatin

Herrera, Salvador C; Sainz de la Maza, Diego; Grmai, Lydia; Margolis, Shally; Plessel, Rebecca; Burel, Michael; O'Connor, Michael; Amoyel, Marc; Bach, Erika A
Aging causes stem cell dysfunction as a result of extrinsic and intrinsic changes. Decreased function of the stem cell niche is an important contributor to this dysfunction. We use the Drosophila testis to investigate what factors maintain niche cells. The testis niche comprises quiescent "hub" cells and supports two mitotic stem cell pools: germline stem cells and somatic cyst stem cells (CySCs). We identify the cell-cycle-responsive Dp/E2f1 transcription factor as a crucial non-autonomous regulator required in CySCs to maintain hub cell quiescence. Dp/E2f1 inhibits local Activin ligands through production of the Activin antagonist Follistatin (Fs). Inactivation of Dp/E2f1 or Fs in CySCs or promoting Activin receptor signaling in hub cells causes transdifferentiation of hub cells into fully functional CySCs. This Activin-dependent communication between CySCs and hub regulates the physiological decay of the niche with age and demonstrates that hub cell quiescence results from signals from surrounding stem cells.
PMID: 34363758
ISSN: 1878-1551
CID: 5004332

The Emerging Roles of JNK Signaling in Drosophila Stem Cell Homeostasis

Herrera, Salvador C; Bach, Erika A
The Jun N-terminal kinase (JNK) pathway is an evolutionary conserved kinase cascade best known for its roles during stress-induced apoptosis and tumor progression. Recent findings, however, have identified new roles for this pleiotropic pathway in stem cells during regenerative responses and in cellular plasticity. Here, we provide an overview of recent findings about the new roles of JNK signaling in stem cell biology using two well-established Drosophila models: the testis and the intestine. We highlight the pathway's roles in processes such as proliferation, death, self-renewal and reprogramming, and discuss the known parallels between flies and mammals.
PMID: 34073743
ISSN: 1422-0067
CID: 4898232

Transcriptomic analysis of feminizing somatic stem cells in the Drosophila testis reveal putative downstream effectors of the transcription factor Chinmo

Grmai, Lydia; Harsh, Sneh; Lu, Sean; Korman, Aryeh; Deb, Ishan B; Bach, Erika A
One of the best examples of sexual dimorphism is the development and function of the gonads, ovaries and testes, which produce sex-specific gametes, oocytes and spermatids, respectively. The development of these specialized germ cells requires sex-matched somatic support cells. The sexual identity of somatic gonadal cells is specified during development and must be actively maintained during adulthood. We previously showed that the transcription factor Chinmo is required to ensure the male sexual identity of somatic support cells in the Drosophila melanogaster testis. Loss of chinmo from male somatic gonadal cells results in feminization: they transform from squamous to epithelial-like cells that resemble somatic cells in the female gonad but fail to properly ensheath the male germline, causing infertility. To identify potential target genes of Chinmo, we purified somatic cells deficient for chinmo from the adult Drosophila testis and performed next-generation sequencing to compare their transcriptome to that of control somatic cells. Bioinformatics revealed 304 and 1,549 differentially upregulated and downregulated genes, respectively, upon loss of chinmo in early somatic cells. Using a combination of methods, we validated several differentially expressed genes. These data sets will be useful resources to the community.
PMID: 33751104
ISSN: 2160-1836
CID: 4822382

Next-Generation Sequencing Reveals Increased Anti-oxidant Response and Ecdysone Signaling in STAT Supercompetitors in Drosophila

Sitaram, Poojitha; Lu, Sean; Harsh, Sneh; Herrera, Salavdor C; Bach, Erika A
Cell competition is the elimination of one viable population of cells (the losers) by a neighboring fitter population (the winners) and was discovered by studies in the Drosophila melanogaster wing imaginal disc. Supercompetition is a process in which cells with elevated JAK/STAT signaling or increased Myc become winners and outcompete wild-type neighbors. To identify the genes that are differentially regulated in STAT supercompetitors, we purified these cells from Drosophila wing imaginal discs and performed next-generation sequencing. Their transcriptome was compared to those of control wing disc cells and Myc supercompetitors. Bioinformatics revealed that STAT and Myc supercompetitors have distinct transcriptomes with only 41 common differentially regulated genes. Furthermore, STAT supercompetitors have elevated reactive oxygen species, an anti-oxidant response and ecdysone signaling. Using a combination of methods, we validated 13 differentially expressed genes. These data sets will be useful resources to the community.
PMID: 31227525
ISSN: 2160-1836
CID: 3939542

Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity

Bailetti, Alessandro A; Negrón-Piñeiro, Lenny J; Dhruva, Vishal; Harsh, Sneh; Lu, Sean; Bosula, Aisha; Bach, Erika A
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of myeloid cells. Most MPN patients have a point mutation in JAK2 (JAK2V617F ), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In Drosophila, this pathway is simplified, with a single JAK, Hopscotch (Hop), and a single STAT transcription factor, Stat92E. The hopTumorous-lethal [hop
PMID: 31072879
ISSN: 1754-8411
CID: 3957852

JAK/STAT signaling in stem cells and regeneration: from Drosophila to vertebrates

Herrera, Salvador C; Bach, Erika A
The JAK/STAT pathway is a conserved metazoan signaling system that transduces cues from extracellular cytokines into transcriptional changes in the nucleus. JAK/STAT signaling is best known for its roles in immunity. However, recent work has demonstrated that it also regulates critical homeostatic processes in germline and somatic stem cells, as well as regenerative processes in several tissues, including the gonad, intestine and appendages. Here, we provide an overview of JAK/STAT signaling in stem cells and regeneration, focusing on Drosophila and highlighting JAK/STAT pathway functions in proliferation, survival and cell competition that are conserved between Drosophila and vertebrates.
PMID: 30696713
ISSN: 1477-9129
CID: 3626652

Super-Competitors Game the Fitness Sensing System

Herrera, Salvador C; Bach, Erika A
Competitive interactions between neighboring cells require fitness comparison and local killing, but the signals regulating these processes are unknown. In this issue, Alpar et al. (2018) demonstrate that fitter cells secrete serine proteases to create a local burst of active Spätzle, triggering Toll signaling and apoptosis in less fit neighbors.
PMID: 30253165
ISSN: 1878-1551
CID: 3314902

JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the Drosophila testis

Herrera, Salvador C; Bach, Erika A
Exhaustion of stem cells is a hallmark of aging. In the Drosophila testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increases during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis-expressing the differentiation factor bag of marbles (bam) in spermatogonia while lineage-labeling these cells. Strikingly, blocking bam-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibiting bam-lineage dedifferentiation markedly reduced the number of GSCs and their ability to proliferate and differentiate. We find that bam-lineage derived GSCs have significantly higher proliferation rates than sibling GSCs in the same testis. We determined that Jun N-terminal kinase (JNK) activity is autonomously required for bam-lineage dedifferentiation. Overall, we show that dedifferentiation provides a mechanism to maintain the germline and ensure fertility under chronically stressful conditions.
PMID: 29985130
ISSN: 2050-084x
CID: 3191762

Chinmo prevents transformer alternative splicing to maintain male sex identity

Grmai, Lydia; Hudry, Bruno; Miguel-Aliaga, Irene; Bach, Erika A
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.
PMID: 29389999
ISSN: 1553-7404
CID: 2933872