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1.
Sci Adv ; 7(51): eabl4391, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34910520

RESUMO

Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFß type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFß family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility.

2.
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
3.
Elife ; 82019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30912742

RESUMO

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Hipófise/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Células-Tronco/fisiologia , Transativadores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Deleção de Genes , Redes Reguladoras de Genes , Camundongos , Hipófise/embriologia , Hipófise/crescimento & desenvolvimento , Fatores de Transcrição SOXB1/análise , Células-Tronco/química , Proteínas de Sinalização YAP
4.
Neurogastroenterol Motil ; 31(4): e13479, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30311722

RESUMO

BACKGROUND: The expression of RET in the developing enteric nervous system (ENS) suggests that RET may contribute to adult intestinal function. ENS cholinergic nerves play a critical role in the control of colonic function through the release of acetylcholine (ACh). In the current study, we hypothesized that a RET-mediated mechanism may regulate colonic ion transport and motility through modulation of cholinergic nerves. METHODS: The effect of RET inhibition on active ion transport was assessed electrophysiologically in rat colonic tissue mounted in Ussing chambers via measurements of short circuit current (Isc) upon electrical field stimulation (EFS) or pharmacologically with cholinergic agonists utilizing a gastrointestinal (GI)-restricted RET inhibitor. We assessed the effect of the RET inhibitor on propulsive motility via quantification of fecal pellet output (FPO) induced by the acetylcholinesterase inhibitor neostigmine. KEY RESULTS: We found that enteric ganglia co-expressed RET and choline acetyltransferase (ChAT) transcripts. In vitro, the RET kinase inhibitor GSK3179106 attenuated the mean increase in Isc induced by either EFS or carbachol but not bethanechol. In vivo, GSK3179106 significantly reduced the prokinetic effect of neostigmine. CONCLUSION AND INFERENCES: Our findings provide evidence that RET-mediated mechanisms regulate colonic function by maintaining cholinergic neuronal function and enabling ACh-evoked chloride secretion and motility. We suggest that modulating the cholinergic control of the colon via a RET inhibitor may represent a novel target for the treatment of intestinal disorders associated with increased secretion and accelerated GI transit such as irritable bowel syndrome with diarrhea (IBS-D).


Assuntos
Neurônios Colinérgicos/efeitos dos fármacos , Colo/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Animais , Colina O-Acetiltransferase/metabolismo , Agonistas Colinérgicos/farmacologia , Neurônios Colinérgicos/metabolismo , Colo/metabolismo , Defecação/efeitos dos fármacos , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Trânsito Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
5.
J Pharmacol Exp Ther ; 368(2): 299-307, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30413627

RESUMO

Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.


Assuntos
Colo/enzimologia , Modelos Animais de Doenças , Síndrome do Intestino Irritável/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Feminino , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Masculino , Camundongos , Camundongos Transgênicos , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
6.
Neuroendocrinology ; 107(2): 196-203, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29539624

RESUMO

As a central regulator of major physiological processes, the pituitary gland is a highly dynamic organ, capable of responding to hormonal demand and hypothalamic influence, through adapting secretion as well as remodelling cell numbers among its seven populations of differentiated cells. Stem cells of the pituitary have been shown to actively generate new cells during postnatal development but remain mostly quiescent during adulthood, where they persist as a long-lived population. Despite a significant body of research characterising attributes of anterior pituitary stem cells, the regulation of this population is poorly understood. A better grasp on the signalling mechanisms influencing stem proliferation and cell fate decisions can impact on our future treatments of pituitary gland disorders such as organ failure and pituitary tumours, which can disrupt endocrine homeostasis with life-long consequences. This minireview addresses the current methodologies aiming to understand better the attributes of pituitary stem cells and the normal regulation of this population in the organ, and discusses putative future avenues to manipulate pituitary stem cells during disease states or regenerative medicine approaches.


Assuntos
Hipófise , Células-Tronco , Animais , Humanos
7.
Front Physiol ; 7: 114, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27065882

RESUMO

The pituitary gland is a primary endocrine organ that controls major physiological processes. Abnormal development or homeostatic disruptions can lead to human disorders such as hypopituitarism or tumors. Multiple signaling pathways, including WNT, BMP, FGF, and SHH regulate pituitary development but the role of the Hippo-YAP1/TAZ cascade is currently unknown. In multiple tissues, the Hippo kinase cascade underlies neoplasias; it influences organ size through the regulation of proliferation and apoptosis, and has roles in determining stem cell potential. We have used a sensitive mRNA in situ hybridization method (RNAscope) to determine the expression patterns of the Hippo pathway components during mouse pituitary development. We have also carried out immunolocalisation studies to determine when YAP1 and TAZ, the transcriptional effectors of the Hippo pathway, are active. We find that YAP1/TAZ are active in the stem/progenitor cell population throughout development and at postnatal stages, consistent with their role in promoting the stem cell state. Our results demonstrate for the first time the collective expression of major components of the Hippo pathway during normal embryonic and postnatal development of the pituitary gland.

8.
Stem Cells ; 33(1): 196-210, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25183173

RESUMO

Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Hipocampo/citologia , Células-Tronco Neurais/citologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , DNA Helicases/biossíntese , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Hipocampo/metabolismo , Humanos , Camundongos , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-17946872

RESUMO

An accurate and robust electroencephalogram (EEG) source localization algorithm would be a definite asset for the surgical treatment of patients with epilepsy. Due to the underdetermined nature of the EEG inverse problem, a variety of algorithms with unique constraints and assumptions are applied to select the current dipole source distribution that best accounts for the scalp recordings. We investigated four algorithms: two non-adaptive algorithms: the minimum norm and LORETA as well as two adaptive algorithms: the Borgiotti-Kaplan and eigenspace projection beamformers. Compared over a range of SNR values and single source locations, we found that the eigenspace projection beamformer exhibited superior localizing capabilities compared to the other three algorithms while minimizing source current dispersion. The size of the data window required to accurately localize using the adaptive beamformers was also investigated to improve algorithm efficiency and minimize stationary source assumptions.


Assuntos
Algoritmos , Mapeamento Encefálico/métodos , Encéfalo/fisiopatologia , Diagnóstico por Computador/métodos , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Cabeça/fisiopatologia , Modelos Neurológicos , Simulação por Computador , Epilepsia/fisiopatologia , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Oncogene ; 23(35): 5958-67, 2004 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-15184868

RESUMO

To identify genes involved in the transformation of thyroid follicular cells, we explored, using DNA oligonucleotide microarrays, the transcriptional response of PC Cl3 rat thyroid epithelial cells to the ectopic expression of the RET/PTC oncogenes. We found that RET/PTC was able to induce the expression of CXCR4, the receptor for the chemokine CXCL12/SDF-1alpha/beta. We observed that CXCR4 expression correlated with the transforming ability of the oncoprotein and depended on the integrity of the RET/PTC-RAS/ERK signaling pathway. We found that CXCR4 was expressed in RET/PTC-positive human thyroid cancer cell lines, but not in normal thyroid cells. Furthermore, we found CXCR4 expression in human thyroid carcinomas, but not in normal thyroid samples by immunohistochemistry. Since CXCR4 has been recently implicated in tumor proliferation, motility and invasiveness, we asked whether treatment with SDF-1alpha was able to induce a biological response in thyroid cells. We observed that SDF-1alpha induced S-phase entry and survival of thyroid cells. Invasion through a reconstituted extracellular matrix was also supported by SDF-1alpha and inhibited by a blocking antibody to CXCR4. Taken together, these results suggest that human thyroid cancers bearing RET/PTC rearrangements may use the CXCR4/SDF-1alpha receptor-ligand pathway to proliferate, survive and migrate.


Assuntos
Carcinoma Papilar/genética , Oncogenes , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Receptores CXCR4/fisiologia , Neoplasias da Glândula Tireoide/genética , Carcinoma Papilar/metabolismo , Sobrevivência Celular , Quimiocina CXCL12 , Quimiocinas CXC/farmacologia , Quimiotaxia/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-ret , Receptores CXCR4/genética , Fase S , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo
12.
J Immunol ; 172(7): 4059-67, 2004 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15034017

RESUMO

RET/PTC3 (RP3) is an oncogenic fusion protein which is frequently expressed in papillary thyroid carcinomas and has been detected in thyroid tissue from patients diagnosed with Hashimoto's thyroiditis. The constitutive activation of the tyrosine kinase domain in the carboxyl-terminal end of RP3 induces signaling pathways within thyrocytes and causes cellular transformation. One of the signaling pathways activated in RP3-expressing cells involves the activity of the transcription factor NF-kappaB and the production of downstream targets including GM-CSF and macrophage chemotactic protein 1. These factors are known to be immunostimulatory, making RP3 a molecular adjuvant and potentially promoting tissue-specific immunity. However compelling, these in vitro data do not reliably predict gene function in vivo or the cumulative effects of time-dependent processes such as angiogenesis, inflammation, or the influence of genetic background. To address these issues, we analyzed the production of proinflammatory mediators in mouse thyroid organs and demonstrate consistency with in vitro studies performed previously that Il1alpha, Il1beta, Il6, and Tnfalpha and the enzyme Cox2 are produced by RP3-transgenic thyroid tissue, but absent from nontransgenic thyroids. Furthermore, we find that that the genetic background of the host is important in the observed RP3-induced inflammation and tumor progression. These findings provide support for the notion that oncogene-induced cytokine secretion is important for the development and progression of thyroid carcinomas in genetically permissive hosts.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Mediadores da Inflamação/fisiologia , Proteínas de Fusão Oncogênica/genética , Proteínas Oncogênicas/genética , Fatores de Transcrição/genética , Animais , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Transformação Celular Neoplásica/patologia , Citocinas/biossíntese , Citocinas/genética , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Progressão da Doença , Mediadores da Inflamação/metabolismo , Leucócitos/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Coativadores de Receptor Nuclear , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Biossíntese de Proteínas , Proteínas/genética , RNA/biossíntese , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/fisiologia
13.
Oncogene ; 22(29): 4569-77, 2003 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-12881713

RESUMO

Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-kappaB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr588; an important protein-binding site for downstream signaling. Together, these studies implicate oncogene-induced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.


Assuntos
Fatores Quimiotáticos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Proteínas Oncogênicas/metabolismo , Glândula Tireoide/metabolismo , Fatores de Transcrição , Animais , Células Cultivadas , Quimiocina CCL2/metabolismo , Citocinas/biossíntese , Fibroblastos/metabolismo , Inflamação/metabolismo , Macrófagos/patologia , Camundongos , Mutação , NF-kappa B/metabolismo , Coativadores de Receptor Nuclear , Proteínas Oncogênicas/genética , Proteínas Tirosina Quinases/metabolismo , Ratos , Transdução de Sinais , Glândula Tireoide/citologia , Glândula Tireoide/transplante
14.
Laryngoscope ; 112(2): 238-42, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11889377

RESUMO

OBJECTIVES: Cyclooxygenases (COX) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. COX-2, unlike the constitutively expressed COX-1, is an inducible enzyme upregulated during cell proliferation and inflammation. More recently, COX-2 has been implicated in the development of numerous types of epithelial cancers. In addition, COX-2 is highly expressed in several inflammatory diseases. Because of its dual role in inflammation and cancer, we were interested in determining if COX-2 plays a role in the development of human thyroid carcinoma and Hashimoto's thyroiditis, an autoimmune condition frequently associated with thyroid malignancy. MATERIALS AND METHODS: Twenty paraffin-embedded human tissue specimens, including normal, inflammatory, and neoplastic thyroid sections, were analyzed by immunohistochemical staining for expression of human COX-2. In addition, COX-2 protein expression was verified by Western blot in two specimens. RESULTS: Immunohistochemical staining confirmed the presence of COX-2 in thyroid epithelial neoplasms, including papillary and follicular carcinomas. Moreover, COX-2 expression was observed in patients with Hashimoto's thyroiditis. COX-2 expression, however, was not observed in normal thyroid tissue, multinodular goiter, or anaplastic carcinoma. CONCLUSIONS: We have shown that cyclooxygenase-2 is expressed in thyroid carcinoma and thyroid epithelium from patients with Hashimoto's thyroiditis but not in normal thyroid. The expression of COX-2 in both of these thyroid pathologies may provide a basis for the relationship between carcinogenesis and autoimmunity.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/enzimologia , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Tireoidite Autoimune/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Western Blotting , Carcinoma/patologia , Técnicas de Cultura , Ciclo-Oxigenase 2 , Feminino , Humanos , Imuno-Histoquímica , Isoenzimas/análise , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Probabilidade , Prostaglandina-Endoperóxido Sintases/análise , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/patologia , Tireoidite Autoimune/patologia
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