Hanfei Zhao, Min Wei, Ruiyan Kong, Zhengran Li, Juan Li, Xihui Yang, Jing Wei, Xieyue Liu Tao, Danjie Zhang, Hang Zhao, Yankun Ma, Ningfang Li, Yudan Wang, Lin Shi, Meifang Ma, Jinjun Wang, Ran Xu, Min Zhang, Yongqiang Wang, Zhouhua Li
{"title":"JAK/STAT下游靶点之间的拮抗作用控制着干细胞增殖、细胞命运转化和肿瘤发生。","authors":"Hanfei Zhao, Min Wei, Ruiyan Kong, Zhengran Li, Juan Li, Xihui Yang, Jing Wei, Xieyue Liu Tao, Danjie Zhang, Hang Zhao, Yankun Ma, Ningfang Li, Yudan Wang, Lin Shi, Meifang Ma, Jinjun Wang, Ran Xu, Min Zhang, Yongqiang Wang, Zhouhua Li","doi":"10.1242/dev.204701","DOIUrl":null,"url":null,"abstract":"<p><p>Proper proliferation and differentiation of adult stem cells maintains tissue homeostasis. However, how cell proliferation and fate conversion are regulated by niche signals remains poorly understood. Here, we systemically identify JAK/STAT downstream targets in adult Drosophila testis using multi-omics approaches. ubr5, encoding an HECT type E3 ligase, is identified as a putative JAK/STAT target. Depletion of ubr5 in somatic cyst cells affects the proliferation and differentiation of cyst stem cell (CySC) and germline stem cell (GSC). Importantly, ubr5-defective CySC-like cells adopt hub cell fate. Mechanistically, UBR5 interacts with Drumstick (Drm), another putative JAK/STAT target, through its UBR domain and mediates Drm poly-ubiquitination for proteolysis. Ectopic expression of drm mimics ubr5-depleted testes and further removal of drm significantly suppresses the defects observed in ubr5-depleted testes. Finally, the function of UBR5 in stem cell regulation is evolutionarily conserved. Collectively, antagonism between JAK/STAT targets controls JAK/STAT signaling duration, stem cell proliferation/differentiation, and cell fate conversion within the testicular niche. Thus our study uncovers the underlying mechanism of how stem cell proliferation and fate conversion are properly controlled during tissue homeostasis and tumorigenesis.</p>","PeriodicalId":11375,"journal":{"name":"Development","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Antagonism between JAK/STAT downstream targets controls stem cell proliferation, cell fate conversion and tumorigenesis.\",\"authors\":\"Hanfei Zhao, Min Wei, Ruiyan Kong, Zhengran Li, Juan Li, Xihui Yang, Jing Wei, Xieyue Liu Tao, Danjie Zhang, Hang Zhao, Yankun Ma, Ningfang Li, Yudan Wang, Lin Shi, Meifang Ma, Jinjun Wang, Ran Xu, Min Zhang, Yongqiang Wang, Zhouhua Li\",\"doi\":\"10.1242/dev.204701\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Proper proliferation and differentiation of adult stem cells maintains tissue homeostasis. However, how cell proliferation and fate conversion are regulated by niche signals remains poorly understood. Here, we systemically identify JAK/STAT downstream targets in adult Drosophila testis using multi-omics approaches. ubr5, encoding an HECT type E3 ligase, is identified as a putative JAK/STAT target. Depletion of ubr5 in somatic cyst cells affects the proliferation and differentiation of cyst stem cell (CySC) and germline stem cell (GSC). Importantly, ubr5-defective CySC-like cells adopt hub cell fate. Mechanistically, UBR5 interacts with Drumstick (Drm), another putative JAK/STAT target, through its UBR domain and mediates Drm poly-ubiquitination for proteolysis. Ectopic expression of drm mimics ubr5-depleted testes and further removal of drm significantly suppresses the defects observed in ubr5-depleted testes. Finally, the function of UBR5 in stem cell regulation is evolutionarily conserved. Collectively, antagonism between JAK/STAT targets controls JAK/STAT signaling duration, stem cell proliferation/differentiation, and cell fate conversion within the testicular niche. Thus our study uncovers the underlying mechanism of how stem cell proliferation and fate conversion are properly controlled during tissue homeostasis and tumorigenesis.</p>\",\"PeriodicalId\":11375,\"journal\":{\"name\":\"Development\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-10-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Development\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1242/dev.204701\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"DEVELOPMENTAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Development","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1242/dev.204701","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
Antagonism between JAK/STAT downstream targets controls stem cell proliferation, cell fate conversion and tumorigenesis.
Proper proliferation and differentiation of adult stem cells maintains tissue homeostasis. However, how cell proliferation and fate conversion are regulated by niche signals remains poorly understood. Here, we systemically identify JAK/STAT downstream targets in adult Drosophila testis using multi-omics approaches. ubr5, encoding an HECT type E3 ligase, is identified as a putative JAK/STAT target. Depletion of ubr5 in somatic cyst cells affects the proliferation and differentiation of cyst stem cell (CySC) and germline stem cell (GSC). Importantly, ubr5-defective CySC-like cells adopt hub cell fate. Mechanistically, UBR5 interacts with Drumstick (Drm), another putative JAK/STAT target, through its UBR domain and mediates Drm poly-ubiquitination for proteolysis. Ectopic expression of drm mimics ubr5-depleted testes and further removal of drm significantly suppresses the defects observed in ubr5-depleted testes. Finally, the function of UBR5 in stem cell regulation is evolutionarily conserved. Collectively, antagonism between JAK/STAT targets controls JAK/STAT signaling duration, stem cell proliferation/differentiation, and cell fate conversion within the testicular niche. Thus our study uncovers the underlying mechanism of how stem cell proliferation and fate conversion are properly controlled during tissue homeostasis and tumorigenesis.
期刊介绍：
Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community.
Development includes a Techniques and Resources section for the publication of new methods, datasets, and other types of resources. Papers describing new techniques should include a proof-of-principle demonstration that the technique is valuable to the developmental biology community; they need not include in-depth follow-up analysis. The technique must be described in sufficient detail to be easily replicated by other investigators. Development will also consider protocol-type papers of exceptional interest to the community. We welcome submission of Resource papers, for example those reporting new databases, systems-level datasets, or genetic resources of major value to the developmental biology community. For all papers, the data or resource described must be made available to the community with minimal restrictions upon publication.
To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.
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