RESUMO
Stem cells can divide asymmetrically with respect to cell fate, producing a copy of themselves (self-renewal), while giving rise to progeny that will differentiate along a specific lineage. Mechanisms that bias the balance towards self-renewal or extend the proliferative capacity of the differentiating progeny can result in tissue overgrowth and, eventually, the formation of tumors. Recent work has explored the role of heterochromatin and heterochromatin-associated proteins in the regulation of stem cell behavior under homeostatic conditions, but less is known about their possible roles in potentiating or suppressing stem cell overproliferation. Here we used ectopic activation of the Jak/STAT pathway in germline and somatic stem cells of the D. melanogaster testis as an in vivo model to probe the function of Heterochromatin Protein 1 (HP1) in stem cell overproliferation. Forced expression of HP1 in either early germ or somatic cells suppressed the overgrowth of testes in response to ectopic Jak/STAT activation. Interestingly, HP1 expression led to distinct phenotypes, depending on whether it was overexpressed in somatic or germ cells, possibly reflecting different cell-autonomous and non-autonomous effects in each cell type. Our results provide a new framework for further in vivo studies aimed at understanding the interactions between heterochromatin and uncontrolled stem cell proliferation, as well as the complex cross-regulatory interactions between the somatic and germline lineages in the Drosophila testis.
Assuntos
Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Células-Tronco/citologia , Testículo/citologia , Animais , Diferenciação Celular , Proteínas Cromossômicas não Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células Germinativas/citologia , Células Germinativas/metabolismo , Janus Quinases/genética , Masculino , Fatores de Transcrição STAT/genética , Transdução de Sinais , Células-Tronco/metabolismo , Testículo/metabolismoRESUMO
The homeostatic turnover of adult organs and their regenerative capacity following injury depend on a careful balance between stem cell self-renewal (to maintain or enlarge the stem cell pool) and differentiation (to replace lost tissue). We have recently characterized the role of the Drosophila Snail family transcription factor escargot (esg) in testis cyst stem cells (CySCs) (1,2) and intestinal stem cells (ISCs). (3,4) CySCs mutant for esg are not maintained as stem cells, but they remain capable of differentiating normally along the cyst cell lineage. In contrast, esg mutant CySCs that give rise to a closely related lineage, the apical hub cells, cannot maintain hub cell identity. Similarly, Esg maintains stemness of ISCs while regulating the terminal differentiation of progenitor cells into absorptive enterocytes or secretory enteroendocrine cells. Therefore, our findings suggest that Esg may play a conserved and pivotal regulatory role in adult stem cells, controlling both their maintenance and terminal differentiation. Here we propose that this dual regulatory role is due to simultaneous control by Esg of overlapping genetic programs and discuss the exciting challenges and opportunities that lie ahead to explore the underlying mechanisms experimentally.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/citologia , Células-Tronco/citologia , Animais , Caderinas/metabolismo , Diferenciação Celular , Drosophila/metabolismo , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Masculino , Células-Tronco/metabolismo , Testículo/citologia , Testículo/metabolismoRESUMO
Tissue stem cells divide to self-renew and generate differentiated cells to maintain homeostasis. Although influenced by both intrinsic and extrinsic factors, the genetic mechanisms coordinating the decision between self-renewal and initiation of differentiation remain poorly understood. The escargot (esg) gene encodes a transcription factor that is expressed in stem cells in multiple tissues in Drosophila melanogaster, including intestinal stem cells (ISCs). Here, we demonstrate that Esg plays a pivotal role in intestinal homeostasis, maintaining the stem cell pool while influencing fate decisions through modulation of Notch activity. Loss of esg induced ISC differentiation, a decline in Notch activity in daughter enteroblasts (EB), and an increase in differentiated enteroendocrine (EE) cells. Amun, an inhibitor of Notch in other systems, was identified as a target of Esg in the intestine. Decreased expression of esg resulted in upregulation of Amun, while downregulation of Amun rescued the ectopic EE cell phenotype resulting from loss of esg. Thus, our findings provide a framework for further comparative studies addressing the conserved roles of Snail factors in coordinating self-renewal and differentiation of stem cells across tissues and species.
Assuntos
Diferenciação Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Animais , DNA Glicosilases/metabolismo , Trato Gastrointestinal/fisiologia , Deleção de Genes , Expressão Gênica , Perfilação da Expressão Gênica , Receptores Notch/metabolismoRESUMO
Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1.
Assuntos
Diferenciação Celular , Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Animais , Trato Gastrointestinal/fisiologia , Deleção de Genes , Expressão Gênica , Perfilação da Expressão GênicaRESUMO
A lot of evidence supports the existence of a monoclonal origin for pituitary tumors, and several genetic alterations have already been confirmed as necessary or sufficient for unrestrained cellular growth and pituitary function. The p53 gene, a known tumor-suppressor gene (TSG), encodes a protein that exerts antiproliferative effects such as cell-growth arrest and apoptosis in response to several types of stimuli. In fact, several human cancers are believed to be caused by p53 mutations. In the case of pituitary tumors, p53 protein accumulation has been described in ACTH-secreting pituitary adenomas. Since increased amounts of the p53 protein are often related to mutations of its gene, we decided to explore the existence of p53 mutations in the tumor tissues of 9 patients bearing non-invasive corticotropinomas, excised by the transphenoidal route. We screened mutations in exons 5 to 8 of the p53 gene by the PCR-SSCP analysis. We were not able to find any mutation in the exons investigated. Our results are in close accordance with those obtained previously for other types of pituitary tumors.