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1.
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
2.
JCI Insight ; 5(23)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108146

RESUMO

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.


Assuntos
Proteínas Relacionadas a Caderinas/genética , Caderinas/genética , Doenças da Hipófise/genética , Adolescente , Animais , Proteínas Relacionadas a Caderinas/metabolismo , Caderinas/metabolismo , Feminino , Humanos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Adulto Jovem
3.
PLoS Comput Biol ; 15(6): e1007030, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194728

RESUMO

Prolactin is a major hormone product of the pituitary gland, the central endocrine regulator. Despite its physiological importance, the cell-level mechanisms of prolactin production are not well understood. Having significantly improved the resolution of real-time-single-cell-GFP-imaging, the authors recently revealed that prolactin gene transcription is highly dynamic and stochastic yet shows space-time coordination in an intact tissue slice. However, it still remains an open question as to what kind of cellular communication mediates the observed space-time organization. To determine the type of interaction between cells we developed a statistical model. The degree of similarity between two expression time series was studied in terms of two distance measures, Euclidean and geodesic, the latter being a network-theoretic distance defined to be the minimal number of edges between nodes, and this was used to discriminate between juxtacrine from paracrine signalling. The analysis presented here suggests that juxtacrine signalling dominates. To further determine whether the coupling is coordinating transcription or post-transcriptional activities we used stochastic switch modelling to infer the transcriptional profiles of cells and estimated their similarity measures to deduce that their spatial cellular coordination involves coupling of transcription via juxtacrine signalling. We developed a computational model that involves an inter-cell juxtacrine coupling, yielding simulation results that show space-time coordination in the transcription level that is in agreement with the above analysis. The developed model is expected to serve as the prototype for the further study of tissue-level organised gene expression for epigenetically regulated genes, such as prolactin.


Assuntos
Comunicação Celular/genética , Modelos Biológicos , Comunicação Parácrina/genética , Animais , Comunicação Celular/fisiologia , Biologia Computacional , Regulação da Expressão Gênica/genética , Humanos , Masculino , Comunicação Parácrina/fisiologia , Hipófise/metabolismo , Prolactina/genética , Prolactina/metabolismo , Ratos , Ratos Transgênicos , Processos Estocásticos
4.
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.

5.
Elife ; 5: e08494, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26828110

RESUMO

Transcription at individual genes in single cells is often pulsatile and stochastic. A key question emerges regarding how this behaviour contributes to tissue phenotype, but it has been a challenge to quantitatively analyse this in living cells over time, as opposed to studying snap-shots of gene expression state. We have used imaging of reporter gene expression to track transcription in living pituitary tissue. We integrated live-cell imaging data with statistical modelling for quantitative real-time estimation of the timing of switching between transcriptional states across a whole tissue. Multiple levels of transcription rate were identified, indicating that gene expression is not a simple binary 'on-off' process. Immature tissue displayed shorter durations of high-expressing states than the adult. In adult pituitary tissue, direct cell contacts involving gap junctions allowed local spatial coordination of prolactin gene expression. Our findings identify how heterogeneous transcriptional dynamics of single cells may contribute to overall tissue behaviour.


Assuntos
Regulação da Expressão Gênica , Hipófise/fisiologia , Transcrição Gênica , Animais , Perfilação da Expressão Gênica , Genes Reporter , Imagem Óptica , Ratos Endogâmicos F344 , Análise Espaço-Temporal
6.
Sci Rep ; 5: 14479, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26411543

RESUMO

In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of ß-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma.


Assuntos
Transformação Celular Neoplásica/metabolismo , Odontoma/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Transformação Celular Neoplásica/genética , Células-Tronco Embrionárias/metabolismo , Feminino , Expressão Gênica , Masculino , Camundongos , Odontogênese/genética , Odontoma/genética , Odontoma/patologia , Gravidez , Fatores de Transcrição SOXB1/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
7.
Endocrinology ; 153(6): 2724-34, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22495675

RESUMO

Prolactin (PRL) is mainly expressed in the pituitary in rodents, whereas in humans, expression is observed in many extrapituitary sites, including lymphocytes. Due to the lack of adequate experimental models, the function of locally produced PRL in the immune system is largely unknown. Using transgenic rats that express luciferase under the control of extensive human PRL regulatory regions, we characterized immune cell responses to thioglycollate (TG)-induced peritonitis. Resident populations of myeloid cells in the peritoneal cavity of untreated rats expressed barely detectable levels of luciferase. In contrast, during TG-induced peritonitis, cell-specific expression in both neutrophils and monocytes/macrophages in peritoneal exudates increased dramatically. Elevated luciferase expression was also detectable in peripheral blood and bone marrow CD11b(+) cells. Ex vivo stimulation of primary myeloid cells showed activation of the human extrapituitary promoter by TNF-α, lipopolysaccharide, or TG. These findings were confirmed in human peripheral blood monocytes, showing that the transgenic rat provided a faithful model for the human gene. Thus, the resolution of an inflammatory response is associated with dramatic activation of the PRL gene promoter in the myeloid lineage.


Assuntos
Células Mieloides/metabolismo , Peritonite/genética , Prolactina/genética , Transcrição Gênica , Animais , Células da Medula Óssea/metabolismo , Antígeno CD11b/metabolismo , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Luciferases/genética , Luciferases/metabolismo , Macrófagos/metabolismo , Microscopia de Fluorescência , Monócitos/metabolismo , Neutrófilos/metabolismo , Peritonite/induzido quimicamente , Peritonite/metabolismo , Prolactina/metabolismo , Ratos , Ratos Transgênicos , Sequências Reguladoras de Ácido Nucleico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tioglicolatos/farmacologia , Tioglicolatos/toxicidade , Fator de Necrose Tumoral alfa/farmacologia
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