Combined Expression of Different Hormone Genes in Single Cells of Normal Rat and Mouse Pituitary

Seuntjens, Eve; Hauspie, Annelies; Roudbaraki, Morad; Vankelecom, Hugo; Denef, Carl

doi:10.1076/apab.110.1.12.904

Cited by 19 publications

(14 citation statements)

References 18 publications

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“…It has been estimated that mammosomatotrophs (cells releasing both PRL and GH) are rela- mice. 23 Overall, the Aip ϩ/Ϫ mouse model greatly resembles the human phenotype reproducing a close to identical tumor phenotype, suggesting that the factors underlying Aipdeficient tumorigenesis are similar in mice and humans. 2,3,5,9 The only major difference observed between the human and mouse phenotype was the complete penetrance of pituitary tumors in mice; all heterozygous mice developed pituitary tumor(s) when aged up till 15 months (Figure 2).…”

Section: Discussionmentioning

confidence: 98%

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

Raitila

Lehtonen

Arola

et al. 2010

The American Journal of Pathology

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Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip ؉/؊ mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIPassociated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas. Pituitary adenomas are common, benign, monoclonal neoplasms of the anterior pituitary gland. They account for approximately 15% of intracranial tumors. Approximately two thirds produce pituitary hormones in excess; among these, prolactin (PRL) and growth hormone (GH)-oversecreting adenomas are the most common. The significant morbidity associated with these lesions arises from the adverse effects of the hypersecretion, such as acromegaly or gigantism in the case of GH secreting adenomas, and/or local compressive effects. 1Mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene have been identified as an underlying cause in human pituitary adenoma predisposition (OMIM 102200), characterized mainly by GH secreting adenomas (somatotropinomas), although susceptibility to PRL (prolactinomas), adrenocorticotropic hormone (ACTH), and nonsecreting adenomas is also part of the disease phenotype. [2][3][4][5] So far AIP mutations have not been associated with any other tumor types.6 -8 Typically, pituitary adenoma predisposition patients have a young age at disease onset but do not necessarily display a strong family history of pituitary adenomas. AIP mutation positive tumors seem to be larger and may have a worse response to somatostatin analogs as compared to sporadic tumors. 4,5,9 Inactivating germline mutations, loss of the normal allele in tumors, as well as recent functional evidence implicate the tumor suppressor role of the AIP gene. 2,5,10 Many of the proteins known to interact with AIP can be linked to tumorigenesis. The best known function of AIP is to stabilize aryl hydrocarbon receptor (AHR) (also known The American Journal of Pathology, Vol. 177, No. 4, October 2010 Copyright © American Society for Investigative P...

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Section: Discussionmentioning

confidence: 98%

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

Raitila

Lehtonen

Arola

et al. 2010

The American Journal of Pathology

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“…In addition, some GH cells become thyrosomatotropes after a thyroidectomy [19] or protracted primary hypothyroidism [33]. Consistently, recent single-cell RT-PCR studies revealed that a large pool of AP cells expressed mRNAs for multiple AP hormones [17,27,28,29,30]. The origin of polyhormonal cells remains obscure.…”

Section: Introductionmentioning

confidence: 93%

Phenotypic characterization of multi-functional somatotropes, mammotropes and gonadotropes of the mouse anterior pituitary

Alonso

Núñez

García‐Sancho

2004

Pflugers Arch - Eur J Physiol

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The existence of bihormonal anterior pituitary (AP) cells co-storing growth hormone and either prolactin (mammosomatotrope) or gonadotropins (somatogonadotrope) has been described. These cells have been proposed to be involved in "paradoxical" secretion [secretion of an AP hormone induced by a non-related hypothalamic releasing factor (HRH) and transdifferentiation (a phenotypic switch between different cell types without cell division]. Here we combine calcium imaging (to assess HRH responsiveness) and multiple sequential immunoassay of the six AP hormones to perform a single-cell phenotypic study of multifunctional somatotropes, mammotropes and gonadotropes in the normal male and female mouse pituitaries. AP cell phenotypes differed from the classic view, showing multiple HRH-receptor expression and/or hormone storage. Mammosomatotropes represented only 5-6% of somatotropes and were poorly responsive to HRHs, suggesting that their contribution to paradoxical secretion should be very limited. Somatogonadotropes were present only in females and contained adrenocorticotropic hormone. They responded to growth hormone-releasing hormone but failed to respond to gonadotropin-releasing hormone (LHRH). Other polyhormonal cells identified include (1) gonadocorticotropes, restricted to females, where they make up more than 50% of all the gonadotropes and contain other AP hormones; (2) gonadomammotropes, which are present preferentially in female cells and respond to LHRH; and (3) gonadothyrotropes, which are present similarly in male and female pituitaries.

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“…In addition, the existence of a cell pool that costores and cosecretes ACTH and TSH during cold stress has been reported (9). Finally, single-cell RT-PCR has also revealed that ϳ30% of pituitary cells display mRNAs for multiple AP hormones (17,(25)(26)(27)(28) in rats, mice, and monkeys. It is remarkable that most of the cells expressing TSH-␤ mRNA (11%) actually costored it with other AP hormone mRNAs (9%), whereas cells expressing only the TSH-␤ mRNA were much less abundant (2%; see Ref.…”

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confidence: 99%

Anterior pituitary thyrotropes are multifunctional cells

Alonso

Núñez

García‐Sancho

2004

American Journal of Physiology-Endocrinology and Metabolism

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Anterior pituitary (AP) contains some unorthodox multifunctional cells that store and secrete two different AP hormones (polyhormonal cells) and/or respond to several hypothalamic-releasing hormones (HRHs; multiresponsive cells). Multifunctional cells may be involved in paradoxical secretion (secretion of a given AP hormone evoked by a noncorresponding HRH) and transdifferentiation (phenotypic switch between different mature cell types without cell division). Here we combine calcium imaging (to assess responses to the four HRHs) and multiple sequential immunoassay of the six AP hormones to perform a single-cell phenotypic study of thyrotropes in normal male and female mice. Surprisingly, most of the thyrotropes were polyhormonal, containing, in addition to thyrotropin (TSH), luteinizing hormone (40 -42%) and prolactin (19 -21%). Thyrotropes costoring growth hormone and/or ACTH were found only in females (24% of each type). These results suggest that costorage of the different hormones does not happen at random and that gender favors certain hormone combinations. Our results indicate that thyrotropes are a mosaic of cell phenotypes rather than a single cell type. The striking promiscuity of TSH storage should originate considerable mix-up of AP hormone secretions on stimulation of thyrotropes. However, response to thyrotropin-releasing hormone was much weaker in the polyhormonal thyrotropes than in the monohormonal ones. This would limit the appearance of paradoxical secretion under physiological conditions and suggests that timing of hormone and HRH receptor expression during the transdifferentiation process is finely and differentially regulated. anterior pituitary; hypothalamic releasing factors; paradoxical secretion THE ANTERIOR PITUITARY (AP) contains five main cell types, somatotropes, mammotropes, corticotropes, thyrotropes, and gonadotropes, which secrete growth hormone (GH), prolactin (PRL), ACTH, thyrotropin (TSH), and gonadotropins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)], respectively. Thyrotropes are the least abundant cell type, amounting to ϳ5-8% of all the AP cells. However, this cell type plays a pivotal role in control of metabolism through regulation of thyroid activity. In the classic view, each AP cell type stores a single hormone in which secretion is specifically regulated by a particular hypothalamic-releasing hormone (HRH). Thus thyrotropes are believed to store and release TSH and express functional thyrotropin-releasing hormone (TRH) receptors involved in hypothalamic control of TSH secretion. However, in the last decade, this "one cell-one hormone" hypothesis has been challenged repeatedly. It has been reported, for example, that many pituitary cells may store and release more than one AP hormone. Mammosomatotropes that store and release GH and PRL (13) have been regarded as an intermediate stage for conversion of somatotropes into mammotropes, a phenotypic switch between mature cell types without cell division called transdifferentiation (13, 31). Polyhormona...

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Combined Expression of Different Hormone Genes in Single Cells of Normal Rat and Mouse Pituitary

Cited by 19 publications

References 18 publications

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

Phenotypic characterization of multi-functional somatotropes, mammotropes and gonadotropes of the mouse anterior pituitary

Anterior pituitary thyrotropes are multifunctional cells

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