Search

As model of organogenesis, the pituitary gland is a relatively simple tissue; yet, we understand little of the mechanisms that determine organ size, cell number and allocation of cells to different lineages. While the discovery of cell-restricted transcription factors has led to significant insight into the mechanisms controlling differentiation and cell-specific gene expression, we still need to integrate these processes with control of organ development. The identification of pituitary stem cells has suggested mechanisms for maintenance of adult pituitary but these findings again highlight the crucial role of cell cycle control for determination of progenitor and differentiated cell numbers. We recently described the mechanisms for progenitor cell cycle exit in early pituitary development that critically depend on the cell cycle inhibitor p57Kip2. It appears that cell cycle control is independent of differentiation, indicating that separate regulatory mechanisms must be involved in each process. The role of p57Kip2 appears to be restricted to progenitor cell cycle exit and it is rather the related p27Kip1 that prevents re-entry into the cycle of differentiated cells. While these data revealed a new transient intermediate between progenitors and differentiated cells, they also raised new questions and suggested that separate signals may control differentiation and cell cycle., (Copyright (c) 2010 S. Karger AG, Basel.)

Patterning and differentiation signals are often believed to drive the developmental program, including cell cycle exit of proliferating progenitors. Taking advantage of the spatial and temporal separation of proliferating and differentiated cells within the developing anterior pituitary gland, we investigated the control of cell proliferation during organogenesis. Thus, we identified a population of noncycling precursors that are uniquely marked by expression of the cell cycle inhibitor p57(Kip2) and by cyclin E. In p57(Kip2-/-) mice, the developing pituitary is hyperplastic due to accumulation of proliferating progenitors, whereas overexpression of p57(Kip2) leads to hypoplasia. p57(Kip2)-dependent cell cycle exit is not required for differentiation, and conversely, blockade of cell differentiation, as achieved in Tpit(-/-) pituitaries, does not prevent cell cycle exit but rather leads to accumulation of p57(Kip2)-positive precursors. Upon differentiation, p57(Kip2) is replaced by p27(Kip1). Accordingly, proliferating differentiated cells are readily detected in p27(Kip1-/-) pituitaries but not in wild-type or p57(Kip2-/-) pituitaries. Strikingly, all cells of p57(Kip2-/-);p27(Kip1-/-) pituitaries are proliferative. Thus, during normal development, progenitor cell cycle exit is controlled by p57(Kip2) followed by p27(Kip1) in differentiated cells; these sequential actions, taken together with different pituitary outcomes of their loss of function, suggest hierarchical controls of the cell cycle that are independent of differentiation.

Pituitary-dependent hyperadrenocorticism (PDH) in dogs is caused by a pituitary corticotroph adenoma. Although PDH is a common disorder in dogs, little is known about the underlying pathogenesis. In the pituitary glands of humans and mice, the pro-opiomelanocortin (POMC)-expressing cell lineages, the corticotrophs and melanotrophs, have a specific marker in common, the T-box transcription factor Tpit (Tbx19), which is obligate for POMC expression. Tpit also regulates the late differentiation of the corticotrophs and melanotrophs, and therefore may contribute to the pathogenesis of the corticotroph adenomas. The aim of this study was to perform an expression and mutation analysis of Tpit in the normal canine pituitary and in corticotroph adenomas. The distribution of the Tpit protein in the pituitary gland was studied with immunohistochemistry and the expression of the gene with RT-PCR. The coding region of Tpit cDNA from 14 dogs with PDH was screened for mutations. Tpit was expressed in corticotroph and melanotroph cells of the normal and adenomatous canine pituitary, and remained present in non-adenomatous corticotrophs of pituitaries from PDH dogs. No tumor-specific mutation in the Tpit cDNA from the corticotroph adenomas was found. However, a missense polymorphism in the highly conserved DNA-binding domain, the T-box, was discovered in one dog. It is concluded that Tpit can be used as a reliable marker for the corticotroph and melanotroph cells in the canine pituitary tissue and that mutations in the Tpit gene are unlikely to play a major role in the pathogenesis of canine corticotroph adenomas.

Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo-pituitary-adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that approximately 50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process.

The pituitary gland orchestrates our endocrine environment: it produces hormones in response to hypothalamic factors that integrate neural inputs and its activity is balanced by the feedback action of peripheral hormones. Disruption of this equilibrium has severe consequences that affect multiple systems and may be fatal. Genetic analysis of pituitary function led to discovery of critical transcription factors that cause hormone deficiencies when mis-expressed. This review will summarize recent findings that led to the first complete clinical description of inherited, isolated corticotropin (ACTH) deficiency (IAD) and to the first molecular mechanism for excessive ACTH production in Cushing’s disease. Indeed, mutations in TPIT, a positive or negative regulator of cell fates for different pituitary lineages, cause neonatal IAD, a condition considered anecdotic before discovery of this transcription factor. Cushing’s disease is caused by corticotroph adenomas that produce excess ACTH as a result of resistance to glucocorticoids (Gc). Molecular investigation of the normal mechanism of Gc feedback led to identification of two essential proteins for pro-opiomelanocortin repression that are often mis-expressed in corticotroph adenomas thus providing a molecular explanation for Gc resistance. These two proteins, Brg1 and histone deacetylase 2 (HDAC2), are involved in chromatin remodeling and may also participate in the tumorigenic process, as Brg1 is a tumor suppressor. These recent advances have provided improved diagnosis and opened new perspectives for patient management and therapies. [ABSTRACT FROM AUTHOR]