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Genetic defects affecting the hypothalamic-pituitary-target organ axes can cause a variety of diseases involving restricted or broad disruptions of human development and physiology. At the level of the anterior pituitary gland, mutations in the genes encoding key transcription factors, hypothalamic releasing and inhibiting hormone receptors, and the pituitary hormones themselves, can all result in the loss of action of one or more of the specialized hormone-secreting cell types. This article focuses on the effects of inherited and sporadic mutations on the development and function of the anterior pituitary. Mutations in the genes encoding the HESX1, PITX2, LHX3, LHX4, PROP1, PIT1, SF1, and TPIT developmental transcription factors are associated with combined pituitary hormone deficiency diseases. By contrast, deleterious alterations in the genes that encode hypothalamic releasing hormone receptors or pituitary hormones, such as the growth hormone releasing hormone receptor or growth hormone genes, usually result in phenotypes that reflect specific defects in the hormone-secreting capacities of individual anterior pituitary cell types.

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF1) exhibit a complex endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and absence of the ventromedial hypothalamic nucleus (VMH). These multiple defects complicate efforts to delineate primary versus secondary effects of SF1 deficiency in different tissues, such that its direct role in gonadotropes remains uncertain. To define this role, we have expressed Cre recombinase driven by the promoter region of the common α subunit of glycoprotein hormones (αGSU), thereby inactivating a loxP-modified SF1 locus in the anterior pituitary gland. Although pituitary-specific SF1 knockout mice were fully viable, they were sterile and failed to develop normal secondary sexual characteristics. Their adrenal glands and VMH appeared normal histologically, but their testes and ovaries were severely hypoplastic. αGSU-Cre, loxP mice had normal levels of most pituitary hormones, but had markedly decreased expression of LH and FSH. Treatment with exogenous gonadotropins stimulated gonadal steroidogenesis, inducing germ cell maturation in males and follicular and uterine maturation in females – establishing that the gonads can respond to gonadotropins. The pituitary-specific SF1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism that establishes essential role(s) of SF1 in pituitary gonadotropes.

Summary: The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (αGSU-Cre), we have previously inactivated steroidogenic factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, αGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts. genesis 30:65–69, 2001. © 2001 Wiley-Liss, Inc.

Organ-specific expression of a cre recombinase transgene allows for the analysis of gene function in a particular tissue or cell type. Using a 4.6 kb promoter from the mouse glycoprotein hormone alpha-subunit (alphaGSU or Cga) gene, we have generated and characterized a line of transgenic mice that express cre recombinase in the anterior and intermediate lobes of the pituitary gland. Utilizing a cre-responsive reporter transgene, alphaGSU-cre transgene expression was detected in the pituitary primordium and in all five cell types of the adult anterior pituitary. alphaGSU-cre transgene activity was also detected in the cardiac and skeletal muscle. Little or no activity was evident in the gonads, adrenal glands, brain, ventromedial hypothalamus, or kidneys. The alphaGSU-cre transgenic mice characterized here will be a valuable tool for examining gene function in the pituitary gland.

BACKGROUND Johnson-McMillin syndrome (JMS) is a rare neuroectodermal disorder characterized by alopecia, ear malformations, conductive hearing loss, anosmia/hyposmia, and hypogonadotropic hypogonadism. It is inherited in an autosomal dominant manner; however, the causative gene has not yet been identified. CASE Herein we report a patient with this condition who exhibits many of the features previously described, including alopecia, malformed auricles, conductive hearing loss, facial asymmetry, and developmental delays. Interestingly, she also has features that have not yet been reported, such as preauricular pits and tags, broad depressions at the lateral aspects of the eyes, and an abnormal left lower eyelid. CONCLUSIONS In addition to demonstrating a pattern of anomalies consistent with JMS, this patient has several unique features. This phenotype supports the involvement of the branchial arches in the embryologic basis of this condition. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.

Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.

Genetic defects affecting the hypothalamic-pituitary-target organ axes can cause a variety of diseases involving restricted or broad disruptions of human development and physiology. At the level of the anterior pituitary gland, mutations in the genes encoding key transcription factors, hypothalamic releasing and inhibiting hormone receptors, and the pituitary hormones themselves, can all result in the loss of action of one or more of the specialized hormone-secreting cell types. This article focuses on the effects of inherited and sporadic mutations on the development and function of the anterior pituitary. Mutations in the genes encoding the HESX1, PITX2, LHX3, LHX4, PROP1, PIT1, SF1, and TPIT developmental transcription factors are associated with combined pituitary hormone deficiency diseases. By contrast, deleterious alterations in the genes that encode hypothalamic releasing hormone receptors or pituitary hormones, such as the growth hormone releasing hormone receptor or growth hormone genes, usually result in phenotypes that reflect specific defects in the hormone-secreting capacities of individual anterior pituitary cell types.

Pituitary gland is a small endocrine gland located at the base of the brain under the optic chiasm and the arachnoid membrane, in a bony indentation called the sella turcica. Its name comes from the Greek hypophysis, which means undergrowth. The role of the pituitary gland is the regulated synthesis and secretion of polypeptide hormones that are essential for the development and function of many other organs in the body. Releasing hormones and inhibiting factors reach the anterior pituitary via hypothalamic neurons that terminate in the capillary beds of the median eminence, just dorsal to the pituitary gland. These capillary beds are connected to the hypophyseal portal vessels that nourish the anterior pituitary. In response to these stimulatory stimulatory factors, pituitary hormones are released into hypophyseal portal blood vessels and carried through the blood stream to their target organs. An intriguing feature of pituitary development is the initial organization of the cell types into discrete patches and the loss of this spatial organization as the organ expands. The rodent pituitary is composed of three lobes. The posterior pituitary (neurohypophysis or pars nervosa) is derived from neural ectoderm and contains the nerve terminals that secrete oxytocin and vasopressin. The intermediate lobe (pars intermedia) and anterior lobe are both derived from oral ectoderm. The bulk of the anterior lobe (pars distaIis) is at the same level as the intermediate lobe, but a portion of it known as the pars tuberalis extends dorsally along the pituitary stalk.

The pituitary gland functions as an intermediary between the brain and the peripheral endocrine organs of the body (Tortora and Grabowski 1996). In the context of a complex system of feedback control, the pituitary gland relays signals from the hypothalamus to its target organs by secreting various hormones. These hormone signals, which are transmitted throughout the endocrine system, reflect the current homeostatic conditions of the body. Mechanisms of compensation, including the regulation of gene transcription, hormone secretion, and cell proliferation, allow the pituitary to respond to the continually changing needs of the organism. It is in this way that the pituitary aids in the regulation of many vital processes, including growth, metabolism, reproduction, and stress response. The mammalian pituitary is comprised of three lobes: the posterior lobe, the intermediate lobe, and the anterior lobe. The anterior lobe of the pituitary is composed of functionally distinct cell types that are the primary site of endocrine regulation. During embryogenesis, the anterior and intermediate lobes of the pituitary develop from an invagination in the oral ectoderm known as Rathke’s pouch (Dubois and ElAmraoui 1995). The pouch eventually separates from the oral ectoderm and undergoes a period of intense proliferation. This is followed by differentiation into the five anterior pituitary cell types on the rostral side of the pouch and the intermediate lobe melanotropes on the caudal side of the pouch (Dubois and Hemming 1991). By birth, the anterior pituitary is composed of functioning corticotropes, thyrotropes, somatotropes, gonadotropes, and lactotropes that produce adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), gonadotropins (FSH and LH), and prolactin (PRL), respectively. Expression of each hormone gene, which defines the terminal differentiation of each cell type, occurs in a spatially and temporally specific manner during pituitary organogenesis (Japon et al. 1994; Burrows et al. 1999). The mechanisms that control this process involve the secretion of signals from surrounding structures and the expression of a cascade of homeodomain transcription factors. Studies in both mouse and human reveal that control of signaling events and homeobox gene expression is essential for proper pituitary gland development (Watkins-Chow and Camper 1998; Dasen and Rosenfeld 1999). Deregulation of these events can lead to various forms of pituitary gland dysfunction, including hypopituitarism and adenomas.