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1.
Proc Natl Acad Sci U S A ; 120(39): e2311130120, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37732755

RESUMO

These are no ordinary times and Piet Borst is no ordinary scientist. In a world challenged by existential threats such as pandemics, climate change and the consequent upsurge in populism, flagrant disinformation, and the global distrust of science and technology, the statesman scientist is a necessary and rare being. Piet Borst has embraced that role for most of his life while remaining a superb biochemist. Borst is this year's winner of the Lasker-Koshland Special Achievement Award in Medical Science "for research accomplishments and scientific statesmanship that engender the deepest feelings of awe and respect".


Assuntos
Distinções e Prêmios , Medicina , Mudança Climática , Desinformação , Emoções
2.
Elife ; 122023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36719070

RESUMO

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.


Assuntos
Jejum Intermitente , Regeneração Hepática , Camundongos , Animais , Fígado , Jejum , Hepatócitos , Proliferação de Células
3.
Methods Mol Biol ; 2544: 171-181, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36125718

RESUMO

Polyploidy is a common and dynamic feature of mature rodent and human hepatocytes. While polyploidization occurs naturally during growth, alterations in the distribution of diploid and polyploid cells in the liver can be indicative of tissue stress or a pathologic state. Here, we describe a method for flow cytometric quantification of ploidy distribution by staining with propidium iodide. We first outline a hepatocyte isolation procedure from mouse liver through a two-step perfusion system for analysis of cellular ploidy. In an alternative approach, we employ a nuclei isolation protocol to assess nuclear ploidy. Finally, we describe how the use of fluorescent cell markers is compatible with these methods and helps retain information on cellular position within the tissue.


Assuntos
Hepatócitos , Ploidias , Animais , Citometria de Fluxo/métodos , Humanos , Fígado , Camundongos , Poliploidia , Propídio
4.
Methods Mol Biol ; 2544: 259-267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36125725

RESUMO

Hepatoblastoma, the most common primary liver malignancy in children, remains poorly understood due in part to a relative lack of methods to expand tumor cells in culture and a paucity of robust experimental models. Here, we describe a method to obtain primary tumor cells from patients with hepatoblastoma and to propagate the cells in 3D culture as tumor organoids, or "tumoroids". We further detail methods to prepare the tumoroids for whole-mount and cross-sectional imaging as well as to perform lentiviral transduction.


Assuntos
Hepatoblastoma , Neoplasias Hepáticas , Criança , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas/patologia , Organoides
5.
Proc Natl Acad Sci U S A ; 119(30): e2203849119, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35867815

RESUMO

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/ß-catenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of E2f7 and E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.


Assuntos
Hepatócitos , Mitose , Proteínas Repressoras , Via de Sinalização Wnt , Animais , Hepatócitos/citologia , Hepatócitos/metabolismo , Camundongos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas com Domínio T/metabolismo , beta Catenina/metabolismo
6.
Annu Rev Biochem ; 91: 571-598, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35303793

RESUMO

The Wnt pathway is central to a host of developmental and disease-related processes. The remarkable conservation of this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity to regulate the generation and spatial arrangement of distinct cell types. By regulating cell fate specification, mitotic activity, and cell polarity, Wnt signaling orchestrates development and tissue homeostasis, and its dysregulation is implicated in developmental defects, cancer, and degenerative disorders. We review advances in our understanding of this key pathway, from Wnt protein production and secretion to relay of the signal in the cytoplasm of the receiving cell. We discuss the evolutionary history of this pathway as well as endogenous and synthetic modulators of its activity. Finally, we highlight remaining gaps in our knowledge of Wnt signal transduction and avenues for future research.


Assuntos
Neoplasias , Via de Sinalização Wnt , Animais , Diferenciação Celular , Neoplasias/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo
7.
Elife ; 102021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33399538

RESUMO

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.


Assuntos
Comunicação Parácrina , Hipófise/fisiologia , Células-Tronco/fisiologia , Via de Sinalização Wnt , Animais , Diferenciação Celular , Proliferação de Células , Feminino , Masculino , Camundongos
8.
Sci Signal ; 12(589)2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289213

RESUMO

Selected members of the Wnt signaling community met during a 4-day period in October 2018 to discuss the current challenges and opportunities associated with targeting the Wnt pathway for therapeutic benefit. A summary of key points of these discussions is presented in this report.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Tanquirases/antagonistas & inibidores , Tanquirases/metabolismo , beta Catenina/metabolismo
9.
Hepatology ; 69(6): 2623-2635, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30762896

RESUMO

In the liver, Wnt/ß-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of ß-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/ß-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.


Assuntos
Proteína Axina/genética , Regeneração Hepática/genética , Fígado/lesões , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Biópsia por Agulha , Tetracloreto de Carbono/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica/genética , Hepatócitos/citologia , Imuno-Histoquímica , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase/métodos , RNA/genética , Distribuição Aleatória , Valores de Referência
10.
Cell ; 175(6): 1607-1619.e15, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30500539

RESUMO

In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah-/- mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.


Assuntos
Antígenos de Diferenciação/biossíntese , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Hepatócitos/metabolismo , Esferoides Celulares/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Linhagem Celular Transformada , Células Hep G2 , Hepatócitos/transplante , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/lesões , Fígado/metabolismo , Camundongos Knockout , Esferoides Celulares/transplante , Fatores de Tempo
11.
Nat Commun ; 9(1): 5078, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30510260

RESUMO

Royal jelly is the queen-maker for the honey bee Apis mellifera, and has cross-species effects on longevity, fertility, and regeneration in mammals. Despite this knowledge, how royal jelly or its components exert their myriad effects has remained poorly understood. Using mouse embryonic stem cells as a platform, here we report that through its major protein component Royalactin, royal jelly can maintain pluripotency by activating a ground-state pluripotency-like gene network. We further identify Regina, a mammalian structural analog of Royalactin that also induces a naive-like state in mouse embryonic stem cells. This reveals an important innate program for stem cell self-renewal with broad implications in understanding the molecular regulation of stem cell fate across species.


Assuntos
Ácidos Graxos/farmacologia , Glicoproteínas/farmacologia , Proteínas de Insetos/farmacologia , Mamíferos/fisiologia , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Células-Tronco Pluripotentes/efeitos dos fármacos , Animais , Abelhas/metabolismo , Cromatina , Ácidos Graxos/química , Feminino , Fertilidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glicoproteínas/química , Proteínas de Insetos/química , Lentivirus/genética , Lentivirus/metabolismo , Longevidade , Camundongos , Modelos Moleculares , Proteínas Recombinantes , Teratoma/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
12.
Development ; 145(12)2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29945986

RESUMO

The history of the Wnt pathway is an adventure that takes us from mice and flies to frogs, zebrafish and beyond, sketching the outlines of a molecular signalling cascade along the way. Here, we specifically highlight the instrumental role that developmental biology has played throughout. We take the reader on a journey, starting with developmental genetics studies that identified some of the main molecular players, through developmental model organisms that helped unravel their biochemical function and cell biological activities. Culminating in complex analyses of stem cell fate and dynamic tissue growth, these efforts beautifully illustrate how different disciplines provided missing pieces of a puzzle. Together, they have shaped our mechanistic understanding of the Wnt pathway as a conserved signalling process in development and disease. Today, researchers are still uncovering additional roles for Wnts and other members of this multifaceted signal transduction pathway, opening up promising new avenues for clinical applications.


Assuntos
Via de Sinalização Wnt , Animais , Drosophila , Desenvolvimento Embrionário , Testes Genéticos , Modelos Animais , Neoplasias/metabolismo , Neoplasias/patologia , Pesquisa Translacional Biomédica
13.
Gynecol Oncol ; 149(2): 388-393, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29544705

RESUMO

OBJECTIVE: Low-grade endometrial stromal sarcomas (LGESS) harbor chromosomal translocations that affect proteins associated with chromatin remodeling Polycomb Repressive Complex 2 (PRC2), including SUZ12, PHF1 and EPC1. Roughly half of LGESS also demonstrate nuclear accumulation of ß-catenin, which is a hallmark of Wnt signaling activation. However, the targets affected by the fusion proteins and the role of Wnt signaling in the pathogenesis of these tumors remain largely unknown. METHODS: Here we report the results of a meta-analysis of three independent gene expression profiling studies on LGESS and immunohistochemical evaluation of nuclear expression of ß-catenin and Lef1 in 112 uterine sarcoma specimens obtained from 20 LGESS and 89 LMS patients. RESULTS: Our results demonstrate that 143 out of 310 genes overexpressed in LGESS are known to be directly regulated by SUZ12. In addition, our gene expression meta-analysis shows activation of multiple genes implicated in Wnt signaling. We further emphasize the role of the Wnt signaling pathway by demonstrating concordant nuclear expression of ß-catenin and Lef1 in 7/16 LGESS. CONCLUSIONS: Based on our findings, we suggest that LGESS-specific fusion proteins disrupt the repressive function of the PRC2 complex similar to the mechanism seen in synovial sarcoma, where the SS18-SSX fusion proteins disrupt the mSWI/SNF (BAF) chromatin remodeling complex. We propose that these fusion proteins in LGESS contribute to overexpression of Wnt ligands with subsequent activation of Wnt signaling pathway and formation of an active ß-catenin/Lef1 transcriptional complex. These observations could lead to novel therapeutic approaches that focus on the Wnt pathway in LGESS.


Assuntos
Neoplasias do Endométrio/genética , Proteínas de Fusão Oncogênica/genética , Sarcoma do Estroma Endometrial/genética , Via de Sinalização Wnt/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Fator 1 de Ligação ao Facilitador Linfoide/biossíntese , Fator 1 de Ligação ao Facilitador Linfoide/genética , Gradação de Tumores , Proteínas de Neoplasias , Proteínas de Fusão Oncogênica/metabolismo , Complexo Repressor Polycomb 2/biossíntese , Complexo Repressor Polycomb 2/genética , Sarcoma do Estroma Endometrial/metabolismo , Sarcoma do Estroma Endometrial/patologia , Análise Serial de Tecidos , Fatores de Transcrição , beta Catenina/biossíntese , beta Catenina/genética
14.
Biophys J ; 113(12): 2762-2767, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29262368

RESUMO

Wnt proteins are secreted, hydrophobic, lipidated proteins found in all animals that play essential roles in development and disease. Lipid modification is thought to facilitate the interaction of the protein with its receptor, Frizzled, but may also regulate the transport of Wnt protein and its localization at the cell membrane. Here, by employing single-molecule fluorescence techniques, we show that Wnt proteins associate with and diffuse on the plasma membranes of living cells in the absence of any receptor binding. We find that labeled Wnt3A transiently and dynamically associates with the membranes of Drosophila Schneider 2 cells, diffuses with Brownian kinetics on flattened membranes and on cellular protrusions, and does not transfer between cells in close contact. In S2 receptor-plus (S2R+) cells, which express Frizzled receptors, membrane diffusion rate is reduced and membrane residency time is increased. These results provide direct evidence of Wnt3A interaction with living cell membranes, and represent, to our knowledge, a new system for investigating the dynamics of Wnt transport.


Assuntos
Membrana Celular/metabolismo , Imagem Óptica , Proteína Wnt3A/metabolismo , Animais , Linhagem Celular , Difusão , Drosophila
15.
Cell Rep ; 21(2): 301-307, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29020617

RESUMO

How do stem cells respond to signals to initiate differentiation? Here, we show that, despite uniform exposure to differentiation-inducing extracellular signals, individual human embryonic stem cells (hESCs) respond heterogeneously. To track how hESCs incipiently exit pluripotency, we established a system to differentiate hESCs as single cells and conducted live imaging to track their very first cell division. We followed the fate of their earliest daughters as they remained undifferentiated or differentiated toward the primitive streak (the earliest descendants of pluripotent cells). About 30%-50% of the time, hESCs divided to yield one primitive streak and one undifferentiated daughter. The undifferentiated daughter cell was innately resistant to WNT signaling and could not respond to this primitive-streak-specifying differentiation signal. Hence, the first division of differentiating hESCs sometimes yields daughters with diverging fates, with implications for the efficiency of directed differentiation protocols and the underlying rules of lineage commitment.


Assuntos
Divisão Celular Assimétrica , Células-Tronco Embrionárias/citologia , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Humanos , Via de Sinalização Wnt
16.
PLoS One ; 12(9): e0184582, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28886197

RESUMO

In the thymus, cortical and medullary thymic epithelial cells (TECs) are instrumental for generating a repertoire of functional T cells. Hence, there has been much interest in the ontogeny of TECs. While medullary TEC (mTEC) and bipotent progenitors have been identified, the existence of a cortical TEC (cTEC) progenitor remains ambiguous. In this study, we used lineage tracing based on a target gene of the Wnt pathway, Axin2. We found that Axin2 initially labels cells in both the cortical and medullary compartments. Using Axin2-CreERT2 mice to track the fate of labelled cells, we identified long-lived cortical TEC progenitors that give rise to expanding clones and contribute to homeostasis in postnatal thymus. In contrast, no clonal expansion was found in the medullary or in the K5K8-double positive compartments. The identification of cTEC progenitors and their regulation by Wnt signaling have important implications for our understanding of thymus physiology during homeostasis and TEC-related disorders.


Assuntos
Proteína Axina/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Timo/citologia , Timo/metabolismo , Animais , Proteína Axina/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem da Célula , Camundongos , Transdução de Sinais/genética
17.
Cell ; 169(6): 985-999, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575679

RESUMO

The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/ß-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.


Assuntos
Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Animais , Anormalidades Congênitas/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Organoides/metabolismo , Células-Tronco/metabolismo , Proteínas Wnt/química , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos
18.
Dev Cell ; 38(6): 643-55, 2016 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-27676437

RESUMO

There were multiple prerequisites to the evolution of multicellular animal life, including the generation of multiple cell fates ("cellular diversity") and their patterned spatial arrangement ("spatial form"). Wnt proteins operate as primordial symmetry-breaking signals. By virtue of their short-range nature and their capacity to activate both lineage-specifying and cell-polarizing intracellular signaling cascades, Wnts can polarize cells at their site of contact, orienting the axis of cell division while simultaneously programming daughter cells to adopt diverging fates in a spatially stereotyped way. By coupling cell fate to position, symmetry-breaking Wnt signals were pivotal in constructing the metazoan body by generating cellular diversity and spatial form.


Assuntos
Evolução Biológica , Linhagem da Célula/genética , Variação Genética , Proteínas Wnt/genética , Divisão Celular/genética , Polaridade Celular/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Transdução de Sinais
19.
Nature ; 524(7564): 180-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26245375

RESUMO

The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity.


Assuntos
Proteína Axina/metabolismo , Diploide , Hepatócitos/citologia , Hepatócitos/metabolismo , Homeostase , Fígado/citologia , Animais , Biomarcadores/metabolismo , Linhagem da Célula , Proliferação de Células , Células Clonais/citologia , Células Clonais/metabolismo , Células Endoteliais/metabolismo , Feminino , Fígado/irrigação sanguínea , Masculino , Camundongos , Poliploidia , Regeneração , Coloração e Rotulagem , Nicho de Células-Tronco/fisiologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/metabolismo , Fatores de Tempo , Veias/citologia , Veias/metabolismo , Via de Sinalização Wnt
20.
Stem Cells ; 33(11): 3356-67, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26220362

RESUMO

The precise role of Wnt/ß-catenin signaling during prostatic development and tumorigenesis is unclear. Axin2 is a direct transcriptional target of ß-catenin. Recent studies have shown that Axin2-expressing cells have stem/progenitor cell properties in a variety of mouse tissues. Here, we genetically labeled Axin2-expressing cells at various time points and tracked their cellular behavior at different developmental and mature stages. We found that prostatic Axin2-expressing cells mainly express luminal epithelial cell markers and are able to expand luminal cell lineages during prostatic development and maturation. They can also survive androgen withdrawal and regenerate prostatic luminal epithelial cells following androgen replacement. Deletion of ß-catenin or expression of stabilized ß-catenin in these Axin2-expressing cells results in abnormal development or oncogenic transformation, respectively. Our study uncovers a critical role of Wnt/ß-catenin-responsive cells in prostatic development and regeneration, and that dysregulation of Wnt/ß-catenin signaling in these cells contributes to prostatic developmental defects and tumorigenesis.


Assuntos
Proteína Axina/biossíntese , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Regeneração/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina/biossíntese , Animais , Linhagem da Célula , Células Epiteliais/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Organogênese/fisiologia , Próstata/citologia
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