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1.
Eur J Endocrinol ; 185(1): 121-135, 2021 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-33950863

RESUMEN

Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.


Asunto(s)
Hipopituitarismo/fisiopatología , Microftalmía/fisiopatología , Neuronas/fisiología , Factores de Transcripción Otx/genética , Hipófisis/fisiopatología , Displasia Septo-Óptica/fisiopatología , Adolescente , Animales , Animales Modificados Genéticamente , Brasil , Línea Celular , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Hipopituitarismo/embriología , Hipopituitarismo/genética , Hipotálamo/citología , Lactante , Masculino , Ratones , Microftalmía/embriología , Microftalmía/genética , Mutación , Neuronas/patología , Linaje , Hipófisis/embriología , Hipófisis/patología , Displasia Septo-Óptica/embriología , Displasia Septo-Óptica/genética , Reino Unido
2.
Gen Comp Endocrinol ; 295: 113524, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32526331

RESUMEN

Early life stages are sensitive to environmental insults and changes during critical developmental periods; this can often result in altered adult behaviour and physiology. Examining the development of the hypothalamus-pituitary-interrenal (HPI) axis and its responsiveness, or lack thereof, during development are important for understanding the short- and long-term impacts of stressors on embryonic and larval fish. We examined the ontogeny of the HPI axis in embryonic (21, 38, 63, 83 and 103 days post-fertilisation (dpf)) and larval (1, 2, 3 and 4 weeks post-hatch (wph)) lake whitefish (Coregonus clupeaformis) by quantifying changes in mRNA levels of several genes associated with HPI axis functioning and whole animal cortisol levels throughout development and in response to a severe or mild hypoxic stress. Cortisol, and crh, crhbp1, pomc and star transcripts were detected from the earliest embryonic age studied. Cortisol levels in control embryos decreased between 21 and 63 dpf, suggesting the utilisation of maternal cortisol deposits. However, by 83 dpf (70% developed) endogenous de novo synthesis had generated a 4.5-fold increase in whole embryo cortisol. Importantly, we provide novel data showing that the HPI axis can be activated even earlier. Whole body cortisol increased in eyed lake whitefish embryos (38 dpf; ~32% developed) in response to hypoxia stress. Coincident with this hypoxia-induced increase in cortisol in 38 dpf embryos were corresponding increases in crh, crhbp1, pomc and star transcript levels. Beyond 38 dpf, the HPI axis in lake whitefish embryos was hyporesponsive to hypoxia stress at all embryonic ages examined (63, 83 and 103 dpf; 54, 72 and 85% developed, respectively). Post-hatch, larvae responded to hypoxia with an increase in cortisol levels and HPI axis genes at 1 wph, but this response was lost and larvae appeared hyporesponsive at subsequent ages (2, 3 and 4 wph). Collectively our work demonstrates that during fish embryogenesis and the larval stage there are windows where the HPI axis is responsive and windows where it is truly hyporesponsive; both could be beneficial in ensuring undisrupted development particularly in the face of increasing environmental changes.


Asunto(s)
Hipotálamo/embriología , Hipoxia/embriología , Lagos , Hipófisis/embriología , Salmonidae/embriología , Animales , Embrión no Mamífero/metabolismo , Desarrollo Embrionario , Hidrocortisona/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Salmonidae/genética
3.
Sci Rep ; 9(1): 5413, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30931985

RESUMEN

The hypothalamus-pituitary-thyroid (HPT) axis plays a crucial role in the metabolism, homeostasis, somatic growth and development of teleostean fishes. Thyroid hormones regulate essential biological functions such as growth and development, regulation of stress, energy expenditure, tissue compound, and psychological processes. Teleost thyroid follicles produce the same thyroid hormones as in other vertebrates: thyroxin (T4) and triiodothyronine (T3), making the zebrafish a very useful model to study hypo- and hyperthyroidism in other vertebrate taxa, including humans. Here we investigate morphological changes in T3 hyperthyroid cases in the zebrafish to better understand malformations provoked by alterations of T3 levels. In particular, we describe musculoskeletal abnormalities during the development of the zebrafish appendicular skeleton and muscles, compare our observations with those recently done by us on the normal developmental of the zebrafish, and discuss these comparisons within the context of evolutionary developmental pathology (Evo-Devo-Path), including human pathologies.


Asunto(s)
Hipertiroidismo/fisiopatología , Músculos/fisiología , Desarrollo Musculoesquelético/fisiología , Glándula Tiroides/fisiología , Animales , Evolución Biológica , Tipificación del Cuerpo/fisiología , Embrión no Mamífero/embriología , Embrión no Mamífero/fisiología , Humanos , Hipertiroidismo/embriología , Hipertiroidismo/metabolismo , Hipotálamo/embriología , Hipotálamo/fisiología , Larva/fisiología , Modelos Animales , Músculos/embriología , Sistema Musculoesquelético/embriología , Hipófisis/embriología , Hipófisis/fisiología , Glándula Tiroides/embriología , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Pez Cebra
4.
Development ; 144(18): 3289-3302, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28807898

RESUMEN

Sonic hedgehog (SHH) is an essential morphogenetic signal that dictates cell fate decisions in several developing organs in mammals. In vitro data suggest that SHH is required to specify LHX3+/LHX4+ Rathke's pouch (RP) progenitor identity. However, in vivo studies have failed to reveal such a function, supporting instead a crucial role for SHH in promoting proliferation of these RP progenitors and for differentiation of pituitary cell types. Here, we have used a genetic approach to demonstrate that activation of the SHH pathway is necessary to induce LHX3+/LHX4+ RP identity in mouse embryos. First, we show that conditional deletion of Shh in the anterior hypothalamus results in a fully penetrant phenotype characterised by a complete arrest of RP development, with lack of Lhx3/Lhx4 expression in RP epithelium at 9.0 days post coitum (dpc) and total loss of pituitary tissue by 12.5 dpc. Conversely, overactivation of the SHH pathway by conditional deletion of Ptch1 in RP progenitors leads to severe hyperplasia and enlargement of the Sox2+ stem cell compartment by the end of gestation.


Asunto(s)
Linaje de la Célula , Proteínas Hedgehog/metabolismo , Hipotálamo/embriología , Hipotálamo/metabolismo , Proteínas con Homeodominio LIM/metabolismo , Hipófisis/embriología , Hipófisis/metabolismo , Factores de Transcripción/metabolismo , Compartimento Celular , Recuento de Células , Diferenciación Celular , Proliferación Celular , Células Clonales , Cruzamientos Genéticos , Ectodermo/embriología , Ectodermo/metabolismo , Embrión de Mamíferos/metabolismo , Endodermo/embriología , Endodermo/metabolismo , Epitelio/embriología , Epitelio/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Genotipo , Proteínas Hedgehog/genética , Humanos , Masculino , Mutación/genética , Hipófisis/patología , Transducción de Señal , Células Madre
5.
Neuroendocrinology ; 105(4): 357-371, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27871073

RESUMEN

BACKGROUND: Kisspeptins are important regulators of the development and function of the hypothalamic-pituitary-gonadal axis. However, the importance of kisspeptin at the pituitary level is unclear. METHODS: We examined the expression profile of kisspeptin in the mouse pituitary during development and in adulthood using RT-PCR, quantitative PCR and immunohistochemistry. RESULTS: Kiss1 mRNA was detected in both embryonic and postnatal pituitaries. Kisspeptin-immunoreactive (+) cells were detected from embryonic day (E) 13.5 throughout adulthood, being localized to the rostroventral portion in the anterior pituitary (AP) in embryos, and also to the dorsocaudal AP postnatally. A large proportion of kisspeptin+ cells were double-labeled with gonadotrope markers including Foxl2, SF-1, and LHß, and the percentage of LHß+ cells in kisspeptin+ cells increased during development. No kisspeptin+ cells were positive for the proliferating cell marker MCM7 (minichromosome maintenance protein 7), but a few kisspeptin+ cells co-expressed the stem/progenitor cell marker Sox2. Kisspeptin expression was similar between sexes and between agonadal SF-1 knockout embryos and wild-type littermates. Kiss1 mRNA levels were not significantly different between sexes or during early postnatal development, but levels in females increased when puberty began and were significantly higher than in males at postpubertal ages. CONCLUSIONS: These results suggest that kisspeptin is expressed in gonadotrope precursors during gonadotrope differentiation, and that kisspeptin expression begins soon after the initiation of αGSU production and is extinguished soon after the initiation of LH production. Furthermore, pituitary kisspeptin expression may be regulated in a gonad-independent manner during development, but may be associated with gonadotrope function in adulthood.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/genética , Gonadotrofos/metabolismo , Hipotálamo , Kisspeptinas/metabolismo , Hipófisis , Factores de Edad , Animales , Animales Recién Nacidos , Embrión de Mamíferos , Femenino , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Kisspeptinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Hipófisis/embriología , Hipófisis/crecimiento & desarrollo , Hipófisis/metabolismo , ARN Mensajero/metabolismo , Factor Esteroidogénico 1/genética , Factor Esteroidogénico 1/metabolismo , Tirotropina de Subunidad beta/metabolismo
6.
PLoS One ; 11(5): e0155762, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27223697

RESUMEN

Di-(2-ethylhexyl) phthalate (DEHP) has the potential to disrupt the thyroid endocrine system, but the underlying mechanism is unknown. In this study, zebrafish (Danio rerio) embryos were exposed to different concentrations of DEHP (0, 40, 100, 200, 400 µg/L) from 2 to 168 hours post fertilization (hpf). Thyroid hormones (THs) levels and transcriptional profiling of key genes related to hypothalamus-pituitary-thyroid (HPT) axis were examined. The result of whole-body thyroxine (T4) and triiodothyronine (T3) indicated that the thyroid hormone homeostasis was disrupted by DEHP in the zebrafish larvae. After exposure to DEHP, the mRNA expressions of thyroid stimulating hormone (tshß) and corticotrophin releasing hormone (crh) genes were increased in a concentration dependent manner, respectively. The expression level of genes involved in thyroid development (nkx2.1 and pax8) and thyroid synthesis (sodium/iodide symporter, nis, thyroglobulin, tg) were also measured. The transcripts of nkx2.1 and tg were significantly increased after DEHP exposure, while those of nis and pax8 had no significant change. Down-regulation of uridinediphosphate-glucuronosyl-transferase (ugt1ab) and up-regulation of thyronine deiodinase (dio2) might change the THs levels. In addition, the transcript of transthyretin (ttr) was up-regulated, while the mRNA levels of thyroid hormone receptors (trα and trß) remained unchanged. All the results demonstrated that exposure to DEHP altered the whole-body thyroid hormones in the zebrafish larvae and changed the expression profiling of key genes related to HPT axis, proving that DEHP induced the thyroid endocrine toxicity and potentially affected the synthesis, regulation and action of thyroid hormones.


Asunto(s)
Dietilhexil Ftalato/toxicidad , Hipotálamo/embriología , Hipófisis/embriología , Glándula Tiroides/embriología , Pez Cebra/embriología , Animales , Hormona Liberadora de Corticotropina/sangre , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Proteínas Nucleares/biosíntesis , Factor de Transcripción PAX8/biosíntesis , Simportadores/biosíntesis , Tiroglobulina/biosíntesis , Factor Nuclear Tiroideo 1 , Tirotropina/sangre , Tiroxina/sangre , Factores de Transcripción/biosíntesis , Triyodotironina/sangre , Proteínas de Pez Cebra/biosíntesis
7.
Endocrinology ; 157(4): 1535-45, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26741195

RESUMEN

Vitamin D (VitD) deficiency affects more than 1 billion people worldwide with a higher prevalence in reproductive-aged women and children. The physiological effects of maternal VitD deficiency on the reproductive health of the offspring has not been studied. To determine whether maternal VitD deficiency affects reproductive physiology in female offspring, we monitored the reproductive physiology of C57BL/6J female offspring exposed to diet-induced maternal VitD deficiency at three specific developmental stages: 1) in utero, 2) preweaning, or 3) in utero and preweaning. We hypothesized that exposure to maternal VitD deficiency disrupts reproductive function in exposed female offspring. To test this hypothesis, we assessed vaginal opening and cytology and ovary and pituitary function as well as gonadotropin and gonadal steroid levels in female offspring. The in utero, preweaning, and in utero and preweaning VitD deficiency did not affect puberty. However, all female mice exposed to maternal VitD deficiency developed prolonged and irregular estrous cycles characterized by oligoovulation and extended periods of diestrus. Despite similar gonadal steroid levels and GnRH neuron density, females exposed to maternal VitD deficiency released less LH on the evening of proestrus. When compared with control female offspring, there was no significant difference in the ability of females exposed to maternal VitD deficiency to respond robustly to exogenous GnRH peptide or controlled ovarian hyperstimulation. These findings suggest that maternal VitD deficiency programs reproductive dysfunction in adult female offspring through adverse effects on hypothalamic function.


Asunto(s)
Sistemas Neurosecretores/fisiopatología , Complicaciones del Embarazo/fisiopatología , Reproducción/fisiología , Deficiencia de Vitamina D/fisiopatología , Animales , Animales Recién Nacidos , Femenino , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiopatología , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Masculino , Ratones Endogámicos C57BL , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Ovario/embriología , Ovario/crecimiento & desarrollo , Ovario/fisiopatología , Hipófisis/embriología , Hipófisis/crecimiento & desarrollo , Hipófisis/fisiopatología , Embarazo , Maduración Sexual/fisiología , Factores de Tiempo , Destete
8.
Handb Clin Neurol ; 124: 3-15, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25248576

RESUMEN

Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and septo-optic dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.


Asunto(s)
Hipotálamo/embriología , Hipotálamo/fisiología , Hipófisis/embriología , Hipófisis/fisiología , Factores de Transcripción/genética , Animales , Genotipo , Humanos , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/metabolismo , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Factores de Transcripción/metabolismo
9.
J Anat ; 221(1): 9-20, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22512474

RESUMEN

The living monotremes (platypus and echidnas) are distinguished by the development of their young in a leathery-shelled egg, a low and variable body temperature and a primitive teat-less mammary gland. Their young are hatched in an immature state and must deal with the external environment, with all its challenges of hypothermia and stress, as well as sourcing nutrients from the maternal mammary gland. The Hill and Hubrecht embryological collections have been used to follow the structural development of the monotreme hypothalamus and its connections with the pituitary gland both in the period leading up to hatching and during the lactational phase of development, and to relate this structural maturation to behavioural development. In the incubation phase, development of the hypothalamus proceeds from closure of the anterior neuropore to formation of the lateral hypothalamic zone and putative medial forebrain bundle. Some medial zone hypothalamic nuclei are emerging at the time of hatching, but these are poorly differentiated and periventricular zone nuclei do not appear until the first week of post-hatching life. Differentiation of the pituitary is also incomplete at hatching, epithelial cords do not develop in the pars anterior until the first week, and the hypothalamo-neurohypophyseal tract does not appear until the second week of post-hatching life. In many respects, the structure of the hypothalamus and pituitary of the newly hatched monotreme is similar to that seen in newborn marsupials, suggesting that both groups rely solely on lateral hypothalamic zone nuclei for whatever homeostatic mechanisms they are capable of at birth/hatching.


Asunto(s)
Hipotálamo , Hipófisis , Ornitorrinco , Tachyglossidae , Animales , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipófisis/embriología , Hipófisis/crecimiento & desarrollo , Ornitorrinco/embriología , Ornitorrinco/crecimiento & desarrollo , Tachyglossidae/embriología , Tachyglossidae/crecimiento & desarrollo
10.
Immunol Res ; 52(1-2): 7-19, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22407539

RESUMEN

There is a growing body of evidence indicating the important role of the neonatal steroid milieu in programming sexually diergic changes in thymopoietic efficiency, which in rodents occur around puberty and lead to a substantial phenotypic and functional remodeling of the peripheral T-cell compartment. This in turn leads to an alteration in the susceptibility to infection and various immunologically mediated pathologies. Our laboratory has explored interdependence in the programming and development of the hypothalamo-pituitary-gonadal axis and thymus using experimental model of neonatal androgenization. We have outlined critical points in the complex process of T-cell development depending on neonatal androgen imprinting and the peripheral outcome of these changes and have pointed to underlying mechanisms. Our research has particularly contributed to an understanding of the putative role of changes in catecholamine-mediated communications in the thymopoietic alterations in adult neonatally androgenized rats.


Asunto(s)
Hormonas Gonadales/metabolismo , Sistema Hipotálamo-Hipofisario/embriología , Sistema Hipotálamo-Hipofisario/metabolismo , Caracteres Sexuales , Timo/embriología , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Catecolaminas , Hipotálamo/embriología , Hipotálamo/metabolismo , Hipófisis/embriología , Hipófisis/metabolismo , Ratas , Receptores Adrenérgicos beta , Transducción de Señal , Linfocitos T/metabolismo , Timo/metabolismo
11.
Hum Mol Genet ; 20(16): 3138-50, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21596839

RESUMEN

CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.


Asunto(s)
Síndrome CHARGE/fisiopatología , Hormona Liberadora de Gonadotropina/metabolismo , Neurogénesis , Reproducción/fisiología , Animales , Síndrome CHARGE/patología , Recuento de Células , Proliferación Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Ciclo Estral/metabolismo , Femenino , Dosificación de Gen/genética , Regulación del Desarrollo de la Expresión Génica , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/sangre , Hipotálamo/embriología , Hipotálamo/metabolismo , Ratones , Neuronas/metabolismo , Neuronas/patología , Nariz/embriología , Nariz/patología , Bulbo Olfatorio/embriología , Bulbo Olfatorio/patología , Hipófisis/embriología , Hipófisis/metabolismo , Pubertad/metabolismo
12.
Endocr Rev ; 30(7): 790-829, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19837867

RESUMEN

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke's pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Hipófisis/embriología , Factores de Transcripción/fisiología , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Regulación de la Expresión Génica/genética , Humanos , Hipotálamo/embriología , Hipotálamo/fisiología , Ratones , Morfogénesis/genética , Morfogénesis/fisiología , Hipófisis/fisiología , Hormonas Hipofisarias/genética , Hormonas Hipofisarias/fisiología , Factores de Transcripción/genética
13.
Gene Expr Patterns ; 9(8): 603-11, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19706338

RESUMEN

In this study, we tested the hypothesis that prostaglandin endoperoxide synthase-1 and -2 (PGHS-1 and PGHS-2) are expressed throughout the latter half of gestation in ovine fetal brain and pituitary. Hypothalamus, pituitary, hippocampus, brainstem, cortex and cerebellum were collected from fetal sheep at 80, 100, 120, 130, 145days of gestational age (DGA), 1 and 7days postpartum lambs, and from adult ewes (n=4-5 per group). mRNA and protein were isolated from each region, and expression of prostaglandin synthase-1 (PGHS-1) and -2 (PGHS-2) were evaluated using real-time RT-PCR and western blot. PGHS-1 and -2 were detected in every brain region at every age tested. Both enzymes were measured in highest abundance in hippocampus and cerebral cortex, and lowest in brainstem and pituitary. PGHS-1 and -2 mRNA's were upregulated in hypothalamus and pituitary after 100 DGA. The hippocampus exhibited decreases in PGHS-1 and increases in PGHS-2 mRNA after 80 DGA. Brainstem PGHS-1 and -2 and cortex PGHS-2 exhibited robust increases in mRNA postpartum, while cerebellar PGHS-1 and -2 mRNA's were upregulated at 120 DGA. Tissue concentrations of PGE(2) correlated with PGHS-2 mRNA, but not to other variables. We conclude that the regulation of expression of these enzymes is region-specific, suggesting that the activity of these enzymes is likely to be critical for brain development in the late-gestation ovine fetus.


Asunto(s)
Sistema Nervioso Central/embriología , Regulación del Desarrollo de la Expresión Génica , Hipófisis/embriología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Animales , Encéfalo/embriología , Tronco Encefálico/embriología , Tronco Encefálico/enzimología , Sistema Nervioso Central/enzimología , Cerebelo/embriología , Cerebelo/enzimología , Ciclooxigenasa 1/biosíntesis , Ciclooxigenasa 1/genética , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/genética , Femenino , Edad Gestacional , Hipotálamo/embriología , Hipotálamo/enzimología , Hipófisis/enzimología , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero , Ovinos
14.
Mol Cell Endocrinol ; 293(1-2): 17-24, 2008 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-18619516

RESUMEN

The ease of in vivo experimental manipulation is one of the main factors that have made the chicken embryo an important animal model in developmental research, including developmental endocrinology. This review focuses on the development of the thyrotropic, corticotropic and somatotropic axes in the chicken, emphasizing the central role of the pituitary gland in these endocrine systems. Functional maturation of the endocrine axes entails the cellular differentiation and acquisition of cell function and responsiveness of the different glands involved, as well as the establishment of top-down and bottom-up anatomical and functional communication between the control levels. Extensive cross-talk between the above-mentioned axes accounts for the marked endocrine changes observed during the last third of embryonic development. In a final paragraph we shortly discuss how genomic resources and new transgenesis techniques can increase the power of the chicken embryo model in developmental endocrinology research.


Asunto(s)
Desarrollo Embrionario , Sistema Endocrino/embriología , Modelos Animales , Animales , Embrión de Pollo , Corticotrofos/fisiología , Retroalimentación Fisiológica , Genómica/métodos , Hipotálamo/embriología , Hipófisis/embriología , Somatotrofos/fisiología , Tirotrofos/fisiología
15.
Best Pract Res Clin Endocrinol Metab ; 22(1): 191-206, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18279788

RESUMEN

The pituitary gland is a complex organ secreting six hormones from five different cell types. It is the end product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism or more complex disorders such as septo-optic dysplasia and holoprosencephaly. However, the overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified; characterization of these will further elucidate the pathogenesis of this complex condition and also shed light on normal pituitary development and function.


Asunto(s)
Hipopituitarismo/congénito , Hipotálamo/embriología , Hipófisis/embriología , Animales , Regulación del Desarrollo de la Expresión Génica , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Hipopituitarismo/genética , Hipotálamo/crecimiento & desarrollo , Ratones , Mutación , Hipófisis/crecimiento & desarrollo , Hormonas Hipofisarias/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
16.
Eur J Endocrinol ; 157 Suppl 1: S3-14, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17785694

RESUMEN

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.


Asunto(s)
Hipopituitarismo/genética , Hipotálamo/embriología , Mutación , Hipófisis/embriología , Hormonas Hipofisarias/deficiencia , Factores de Transcripción/genética , Animales , Humanos , Prosencéfalo/embriología , Factores de Transcripción/metabolismo
17.
Semin Cell Dev Biol ; 18(4): 559-70, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17509912

RESUMEN

Hormone balances in the body are primarily governed by the hypothalamus-pituitary system. For its pivotal role, the pituitary gland relies on an assortment of different hormone-producing cell types, the proportions of which dynamically change in response to fluctuating endocrine demands. Mechanisms of pituitary cellular plasticity are at present far from understood, and may include proliferation and transdifferentiation of hormonal cells. Whether new cells also originate by recruitment from stem cells is unsettled, although this idea has frequently been proposed. Here, I will review these data by focusing on the non-hormonal cell types that have been advanced as candidates for the pituitary stem cell position.


Asunto(s)
Hipotálamo/embriología , Hipófisis/embriología , Células Madre/fisiología , Animales , Hipotálamo/citología , Hipófisis/citología
18.
An. pediatr. (2003, Ed. impr.) ; 66(supl.1): 53-63, abr. 2007. ilus
Artículo en Español | IBECS | ID: ibc-145343

RESUMEN

Se realiza una revisión de los aspectos de imagen del eje hipófisis-hipotálamo en la edad pediátrica, haciendo unas consideraciones de esta técnica de imagen en sus indicaciones actuales. Se describe las indicaciones más frecuentes que incluyen malformaciones congénitas, inflamaciones, procesos autoinmunes, tumorales y las indicaciones endocrinas más frecuentemente requeridas en pediatría. Finalmente se comentarán brevemente los riesgos, efectividad y comparación con otros métodos (AU)


No disponible


Asunto(s)
Humanos , Enfermedades Hipotalámicas/fisiopatología , Sistema Hipotálamo-Hipofisario/fisiopatología , Espectroscopía de Resonancia Magnética , Hipotálamo/embriología , Hipófisis/embriología , Neoplasias Encefálicas/complicaciones
19.
J Chem Neuroanat ; 33(1): 34-41, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17134871

RESUMEN

The maternal environment affects fetal development and may permanently affect the physiology of the adult. Fetal growth hormone (GH) secretion is increased by maternal undernutrition but the physiological mechanisms responsible for this increase are unknown. We have recently found evidence suggesting that the GHRH component of the fetal neuroendocrine GH axis may be perturbed by undernutrition. This study sought to determine the effect of maternal undernutrition on immunocytochemically detectable GHRH neurons and the expression of GHRH receptors by somatotropes in the pituitary gland. Ewes were grouped (n=12 per group) randomly into control (fed 100% of requirements) or nutrient restricted (fed 50% of requirements) from days 28 to 78 of gestation, corresponding to the period from implantation to the end of placentation. At day 78, half the ewes were killed and the fetal brains were perfused. The remaining ewes were re-alimented to 100% of nutritional requirements and killed at day 135. There was no effect of nutrition restriction or age on the number of GHRH neurons. Similarly, the mean density and percentage of somatotropes expressing GHRH receptors was not significantly different between treatment groups at either age. This study found no effect, as determined by immunocytochemistry, of nutrient restriction on the GHRH component of the fetal neuroendocrine GH axis. It remains to be established if the release of GHRH and responsiveness of somatotropes to GHRH in the fetus are affected by undernutrition.


Asunto(s)
Desarrollo Fetal , Privación de Alimentos , Regulación del Desarrollo de la Expresión Génica , Hormona Liberadora de Hormona del Crecimiento/fisiología , Neuronas/metabolismo , Receptores de Neuropéptido/fisiología , Receptores de Hormona Reguladora de Hormona Hipofisaria/fisiología , Somatotrofos/metabolismo , Animales , Femenino , Hipotálamo/embriología , Inmunohistoquímica , Intercambio Materno-Fetal , Hipófisis/embriología , Embarazo , Ovinos
20.
J Soc Gynecol Investig ; 13(5): 329-37, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16753312

RESUMEN

OBJECTIVE: Nitric oxide (NO) is synthesized in the brain through the action of three isoforms of nitric oxide synthase (NOS). The local generation of NO in neurons, glia, and vasculature modulates neuronal activity, as well as regional cerebral blood flow. We propose that, in the fetal brain, cerebral hypoperfusion alters the expression of NOS isoforms, and that estrogen administration modulates the NOS response to hypoperfusion. METHODS: Sixteen chronically catheterized fetal sheep of known gestational age (124 to 128 days' gestation) were subjected to a 10-minute period of brachiocephalic occlusion (BCO) or to sham BCO; half of these fetuses were subjected to subcutaneous implant, which released 17beta-estradiol (E2; 0.25 mg/d) or placebo. Brain tissue was collected for mRNA and protein extraction 1 hour after the start of the BCO or sham BCO. RESULTS: All three isoforms of NOS were identified in fetal brain at both the mRNA and protein levels. BCO increased NOS1 (hippocampus, brainstem), NOS2 (hypothalamus), and NOS3 (hippocampus, cortex) at the protein level. Estradiol alone increased NOS1 (brainstem, cortex), NOS2 (hippocampus, hypothalamus), and NOS3 (brainstem, cerebellum) at the protein level, changes that were not mirrored at the mRNA level. The combination of BCO and estradiol produced smaller changes in NOS1 (brainstem, cortex), NOS2 (hippocampus, hypothalamus), and NOS3 (brainstem) protein levels than those produced by either stimulus alone. CONCLUSIONS: We conclude that the fetal brain expresses all isoforms of NOS, and that NOS expression is altered by both BCO and estradiol, but that the most prevalent effect of estradiol is to reduce specific NOS responses to cerebral hypoperfusion. The present results suggest the possibility that the neuroendocrine responses to estradiol and BCO are modulated by central nervous system (CNS) NO biosynthesis.


Asunto(s)
Encéfalo/embriología , Encéfalo/enzimología , Estradiol/administración & dosificación , Hemodinámica , Óxido Nítrico Sintasa/genética , Ovinos/embriología , Animales , Tronco Encefálico/enzimología , Corteza Cerebral/enzimología , Expresión Génica/efectos de los fármacos , Edad Gestacional , Hipocampo/enzimología , Hipotálamo/enzimología , Isoenzimas/análisis , Isoenzimas/genética , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa de Tipo I/análisis , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo II/análisis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo III/análisis , Óxido Nítrico Sintasa de Tipo III/genética , Hipófisis/embriología , Hipófisis/enzimología , Placebos , ARN Mensajero/análisis
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