Navegar

Colección

Datos Estadísticas

Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Recently, the importance of the dopaminergic D2 receptor (D2R) subtype in normal body growth and neonatal GH secretion has been highlighted. Disruption of D2R alters the GHRH-GH-IGF-I axis and impairs body growth in adult male mice. The D2R knockout (KO) dwarf mouse has not been well characterized; we therefore sought to determine somatotrope function in the adult pituitary. Using immunohistochemistry and confocal microscopy, we found a significant decrease in the somatotrope population in pituitaries from KO mice (P=0.043), which was paralleled by a decreased GH output from pituitary cells cultured in vitro. In cells from adult mice the response amplitude to GHRH differed between genotypes (lower in KO), but this difference was less dramatic after taking into account the lower basal release and hormone content in the KO cells. Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes. By Western blot, GHRH-receptor in pituitary membranes from KO mice was reduced to 46% of the level found in wildtype (WT) mice (P=0.016). Somatostatin induced a concentration-dependent decrease in GH and prolactin (PRL) secretion in both genotypes, and 1 × 10-7 M ghrelin released GH in cells from both genotypes (P=0.017) in a proportionate manner to basal levels. These results suggest that KO somatotropes maintain a regulated secretory function. Finally, we tested the direct effect of dopamine on GH and PRL secretion in cells from both genotypes at 20 days and 6 months of life. As expected, we found that dopamine could reduce PRL levels at both ages in WT mice but not in KO mice, but there was no consistent effect of the neurotransmitter on GH release in either genotype at the ages studied. The present study demonstrates that in the adult male D2R KO mouse, there is a reduction in pituitary GH content and secretory activity. Our results point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level either in 1-month-old or adult mice. The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism. A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population. Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function. © 2006 Society for Endocrinology.

Registro:

Documento: Artículo
Título:GH in the dwarf dopaminergic D2 receptor knockout mouse: Somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin
Autor:García-Tornadú, I.; Rubinstein, M.; Gaylinn, B.D.; Hill, D.; Arany, E.; Low, M.J.; Díaz-Torga, G.; Becu-Villalobos, D.
Filiación:Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), University of Buenos Aires, V. Obligado 2490, 1428 Buenos Aires, Argentina
UVA Health System, Charlottesville, VA, United States
Lawson Health Research Institute, London, ON, Canada
Center for the Study of Weight Regulation, Oregon Health and Science University, Portland, OR, United States
Palabras clave:cyclic AMP; dopamine; dopamine 2 receptor; ghrelin; growth hormone; growth hormone releasing factor; growth hormone releasing factor receptor; neurotransmitter; prolactin; somatostatin; animal cell; animal experiment; animal model; animal tissue; article; cell count; cell culture; concentration (parameters); confocal microscopy; controlled study; genotype; growth hormone release; hormonal regulation; hormone action; hypophysis cell; hypothalamus; immunohistochemistry; in vivo study; knockout mouse; male; molecular mechanics; mouse; nonhuman; pituitary dwarfism; priority journal; prolactin release; sensitivity analysis; signal transduction; Western blotting; wild type; Animals; Blotting, Western; Cells, Cultured; Cyclic AMP; Dopamine; Dose-Response Relationship, Drug; Dwarfism; Ghrelin; Growth Hormone; Growth Hormone-Releasing Hormone; Immunohistochemistry; Male; Mice; Mice, Knockout; Microscopy, Confocal; Peptide Hormones; Pituitary Gland; Prolactin; Receptors, Dopamine D2; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Somatostatin
Año:2006
Volumen:190
Número:3
Página de inicio:611
Página de fin:619
DOI: http://dx.doi.org/10.1677/joe.1.06902
Título revista:Journal of Endocrinology
Título revista abreviado:J. Endocrinol.
ISSN:00220795
CODEN:JOENA
CAS:cyclic AMP, 60-92-4; dopamine, 51-61-6, 62-31-7; ghrelin, 258279-04-8, 304853-26-7; growth hormone, 36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6; growth hormone releasing factor, 83930-13-6, 9034-39-3; prolactin, 12585-34-1, 50647-00-2, 9002-62-4; somatostatin, 38916-34-6, 51110-01-1; Cyclic AMP, 60-92-4; Dopamine, 51-61-6; Ghrelin; Growth Hormone, 9002-72-6; Growth Hormone-Releasing Hormone, 9034-39-3; Peptide Hormones; Prolactin, 9002-62-4; Receptors, Dopamine D2; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Somatostatin, 51110-01-1; ghrelin; somatotropin releasing hormone receptor
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00220795_v190_n3_p611_GarciaTornadu

Referencias:

  • Asa, S.L., Kelly, M.A., Grandy, D.K., Low, M.J., Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice (1999) Endocrinology, 140, pp. 5348-5355
  • Behringer, R.R., Mathews, L.S., Palmiter, R.D., Brinster, R.L., Dwarf mice produced by genetic ablation of growth hormone-expressing cells (1988) Genes and Development, 2, pp. 453-461
  • Ben-Jonathan, N., Hnasko, R., Dopamine as a prolactin (PRL) inhibitor (2001) Endocrine Reviews, 22, pp. 724-763
  • Bluet-Pajot, M.T., Mounier, F., Durand, D., Kordon, C., Involvement of dopamine D1 receptors in the control of growth hormone secretion in the rat (1990) Journal of Endocrinology, 127, pp. 191-196
  • Carmignac, D.F., Bennett, P.A., Robinson, I.C., Effects of growth hormone secretagogues on prolactin release in anesthetized dwarf (dw/dw) rats (1998) Endocrinology, 139, pp. 3590-3596
  • Cella, S.G., Locatelli, V., Broccia, M.L., Menegola, E., Giavini, E., De Gennaro Colonna, V., Torsello, A., Muller, E.E., Long-term changes of somatotrophic function induced by deprivation ofgrowth hormone-releasing hormone during the fetal life of the rat (1994) Journal of Endocrinology, 140, pp. 111-117
  • Cristina, C., Diaz-Torga, G., Balch, A., Gongora, A., Rubinstein, M., Low, M.J., Becu-Villalobos, D., Increased pituitary vascular endothelial growth factor-A in dopaminergic D2 receptor knockout female mice (2005) Endocrinology, 146, pp. 2952-2962
  • Del Punta, K., Charreau, E., Pignataro, O.P., Nitric oxide inhibits Leydig cell steroidogenesis (1996) Endocrinology, 137, pp. 5337-5343
  • Diaz-Torga, G., Feierstein, C., Libertun, C., Gelman, D., Kelly, M.A., Low, M.J., Rubinstein, M., Becu-Villalobos, D., Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice (2002) Endocrinology, 143, pp. 1270-1279
  • Eicher, E.M., Beamer, W.G., Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6 (1976) Journal of Heredity, 67, pp. 87-91
  • Eicher, E.M., Beamer, W.G., New mouse dw allele: Genetic location and effects on lifespan and growth hormone levels (1980) Journal of Heredity, 71, pp. 187-190
  • Flavell, D.M., Wells, T., Wells, S.E., Carmignac, D.F., Thomas, G.B., Robinson, I.C., Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons (1996) EMBO Journal, 15, pp. 3871-3879
  • Gaylinn, B.D., Lyons, C.E., Zysk, J.R., Clarke, I.J., Thorner, M.O., Photoaffinity cross-linking to the pituitary receptor for growth hormone-releasing factor (1994) Endocrinology, 135, pp. 950-955
  • Gaylinn, B.D., Dealmeida, V.I., Lyons Jr., C.E., Wu, K.C., Mayo, K.E., Thorner, M.O., The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH/ (1999) Endocrinology, 140, pp. 5066-5074
  • Gonzalez Iglesias, A., Diaz-Torga, G., Piroli, G., Achaval-Zaia, R., De Nicola, A.F., Libertun, C., Becu-Villalobos, D., Bromocriptine restores Angiotensin II response in pituitary hyperplasia (2000) Molecular and Cellular Endocrinology, 165, pp. 67-74
  • Kamegai, J., Unterman, T.G., Frohman, L.A., Kineman, R.D., Hypothalamic/pituitary-axis of the spontaneous dwarf rat: Autofeedback regulation of growth hormone (GH) includes suppression of GH releasing-hormone receptor messenger ribonucleic acid (1998) Endocrinology, 139, pp. 3554-3560
  • Kelly, M.A., Rubinstein, M., Asa, S.L., Zhang, G., Saez, C., Bunzow, J.R., Allen, R.G., Grandy, D.K., Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice (1997) Neuron, 19, pp. 103-113
  • Kineman, R.D., Aleppo, G., Frohman, L.A., The tyrosine hydroxylase-human growth hormone (GH) transgenic mouse as a model of hypothalamic GH deficiency: Growth retardation is the result of a selective reduction in somatotrope numbers despite normal somatotrope function (1996) Endocrinology, 137, pp. 4630-4636
  • Li, S., Crenshaw, E.B., Rawson, E.J., Simmons, D.M., Swanson, L.W., Rosenfeld, M.G., Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene Pit-1 (1990) Nature, 347, pp. 528-533
  • Lin, S.C., Lin, C.R., Gukovsky, I., Lusis, A.J., Sawchenko, P.E., Rosenfeld, M.G., Molecular basis of the little mouse phenotype and implications for cell type-specific growth (1993) Nature, 364, pp. 208-213
  • Missale, C., Nash, S.R., Robinson, S.W., Jaber, M., Caron, M.G., Dopamine receptors: From structure to function (1998) Physiological Reviews, 78, pp. 189-225
  • Müller, E., Locatelli, V., Cocchi, D., Neuroendocrine control of growth hormone secretion (1999) Physiological Reviews, 79, pp. 511-607
  • Niimi, M., Takahara, J., Sato, M., Kawanishi, K., Identification of dopamine and growth hormone-releasing factor-containing neurons projecting to the median eminence of the rat by combined retrograde tracing and immunohistochemistry (1992) Neuroendocrinology, 55, pp. 92-96
  • Phelps, C.J., Hurley, D.L., Pituitary hormones as neurotrophic signals: Update on hypothalamic differentiation in genetic models of altered feedback (1999) Proceeding of the Society of Experimental Biology and Medicine, 222, pp. 39-58
  • Phelps, C.J., Romero, M.I., Hurley, D.L., Growth hormone-releasing hormone-producing and dopaminergic neurones in the mouse arcuate nucleus are independently regulated populations (2003) Journal of Neuroendocrinology, 15, pp. 280-288
  • Robinson, G.M., Spencer, G.S., Berry, C.J., Dobbie, P.M., Hodgkinson, S.C., Bass, J.J., Evidence of a role for growth hormone, but not for insulin-like growth factors-I and -II in the growth of the neonatal rat (1993) Biology of the Neonate, 64, pp. 158-165
  • Rocheville, M., Lange, D.C., Kumar, U., Patel, S.C., Patel, R.C., Patel, Y.C., Receptors for dopamine and somaxostatin: Formation of hetero-oligomers with enhanced functional activity (2000) Science, 288, pp. 154-157
  • Sato, A., Shioda, S., Nakai, Y., Catecholaminergic innervation of GRF-containing neurons in the rat hypothalamus revealed by electron-microscopic cytochemistry (1989) Cell and Tissue Research, 258, pp. 31-34
  • Schriock, E.A., Lustig, R.H., Rosenthal, S.M., Kaplan, S.L., Grumbach, M.M., Effect of growth hormone (GH)-releasing hormone (GRH) on plasma GH in relation to magnitude and duration of GH deficiency in 26 children and adults with isolated GH deficiency or multiple pituitary hormone deficiencies: Evidence for hypothalamic GRH deficiency (1984) Journal of Clinical Endocrinology and Metabolism, 58, pp. 1043-1049
  • Smith, R.G., Development of growth hormone secretagogues (2005) Endocrine Reviews, 26, pp. 346-360
  • Sornson, M.W., Wu, W., Dasen, J.S., Flynn, S.E., Norman, D.J., O'Connell, S.M., Gukovsky, I., Miller, A.P., Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism (1996) Nature, 384, pp. 327-333
  • Szabo, M., Butz, M.R., Banerjee, S.A., Chikaraishi, D.M., Frohman, L.A., Autofeedback suppression of growth hormone (GH) secretion in transgenic once expressing a human GH reporter targeted by tyrosine hydroxylase 5′-flanking sequences to the hypothalamus (1995) Endocrinology, 136, pp. 4044-4048
  • Tierney, T., Robinson, I.C.A.F., Increased lactotrophs despite decresed somatotrophs in the dwarf (dw/dw) rat: A defect in the regulation of lactotroph/somatotroph cell fate? (2002) Journal of Endocrinology, 175, pp. 435-446
  • Wettschureck, N., Moers, A., Wallenwein, B., Parlow, A.E., Maser-Gluth, C., Offermanns, S., Loss of Gq/11 family G proteins in the nervous system causes pituitary somatotroph hypoplasia and dwarfism in mice (2005) Molecular and Cellular Biology, 25, pp. 1942-1948
  • Zhou, Y., Xu, B.C., Maheshwari, H.G., He, L., Reed, M., Lozykowski, M., Okada, S., Wagner, T.E., A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse) (1997) PNAS, 94, pp. 13215-13220
  • Zoli, M., Agnati, L.F., Tinner, B., Steinbusch, H.W., Fuxe, K., Distribution of dopamine-immunoreactive neurons and their relationships to transmitter and hypothalamic hormone-immunoreactive neuronal systems in the rat mediobasal hypothalamus. A morphometric and microdensitometric analysis (1993) Journal of Chemical Neuroanatomy, 6, pp. 293-310

Citas:

---------- APA ----------
García-Tornadú, I., Rubinstein, M., Gaylinn, B.D., Hill, D., Arany, E., Low, M.J., Díaz-Torga, G.,..., Becu-Villalobos, D. (2006) . GH in the dwarf dopaminergic D2 receptor knockout mouse: Somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin. Journal of Endocrinology, 190(3), 611-619.
http://dx.doi.org/10.1677/joe.1.06902
---------- CHICAGO ----------
García-Tornadú, I., Rubinstein, M., Gaylinn, B.D., Hill, D., Arany, E., Low, M.J., et al. "GH in the dwarf dopaminergic D2 receptor knockout mouse: Somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin" . Journal of Endocrinology 190, no. 3 (2006) : 611-619.
http://dx.doi.org/10.1677/joe.1.06902
---------- MLA ----------
García-Tornadú, I., Rubinstein, M., Gaylinn, B.D., Hill, D., Arany, E., Low, M.J., et al. "GH in the dwarf dopaminergic D2 receptor knockout mouse: Somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin" . Journal of Endocrinology, vol. 190, no. 3, 2006, pp. 611-619.
http://dx.doi.org/10.1677/joe.1.06902
---------- VANCOUVER ----------
García-Tornadú, I., Rubinstein, M., Gaylinn, B.D., Hill, D., Arany, E., Low, M.J., et al. GH in the dwarf dopaminergic D2 receptor knockout mouse: Somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin. J. Endocrinol. 2006;190(3):611-619.
http://dx.doi.org/10.1677/joe.1.06902