The origins of the circumventricular organs.

The circumventricular organs (CVOs) are specialised neuroepithelial structures found in the midline of the brain, grouped around the third and fourth ventricles. They mediate the communication between the brain and the periphery by performing sensory and secretory roles, facilitated by increased vascularisation and the absence of a blood-brain barrier. Surprisingly little is known about the origins of the CVOs (both developmental and evolutionary), but their functional and organisational similarities raise the question of the extent of their relationship. Here, I review our current knowledge of the embryonic development of the seven major CVOs (area postrema, median eminence, neurohypophysis, organum vasculosum of the lamina terminalis, pineal organ, subcommissural organ, subfornical organ) in embryos of different vertebrate species. Although there are conspicuous similarities between subsets of CVOs, no unifying feature characteristic of their development has been identified. Cross-species comparisons suggest that CVOs also display a high degree of evolutionary flexibility. Thus, the term 'CVO' is merely a functional definition, and features shared by multiple CVOs may be the result of homoplasy rather than ontogenetic or phylogenetic relationships.

A case of presumably Rathke's cleft cyst associated with postoperative cerebrospinal fluid leakage through persisting embryonal infundibular recess.

Persisting embryonal infundibular recess (PEIR) is a rare anomaly of the third ventricular floor. Only eight cases have been published. In this report, a case of presumably Rathke's cleft cyst associated with cerebrospinal fluid leakage caused by PEIR is described. An 81-year-old woman underwent endoscopic transsphenoidal surgery for the intra- and supra-sellar cystic lesion. Intraoperatively a hole was confirmed over the sella turcica connecting the sellar cyst and the infundibular recess. Liquorrhea did not occur throughout the procedure. A computed tomography (CT) scan obtained immediately after surgery disclosed accumulation of air in the third and lateral ventricles, in addition to the intra- and supra-sellar region. Air accumulation resolved spontaneously after bed rest for 11 days and she was discharged without neurological deficits. However, she required the second transsphenoidal surgery to repair the sellar floor because of bacterial meningitis caused by liquorrhea on the postoperative day 23. A postoperative 3-tesla magnetic resonance image revealed a deep infundibular recess connecting the sella turcica and the third ventricle, which was considered to be PEIR. To the best our knowledge, this is the first reported case describing the intraoperative findings of PEIR.

Direct and indirect roles of Fgf3 and Fgf10 in innervation and vascularisation of the vertebrate hypothalamic neurohypophysis.

The neurohypophysis is a crucial component of the hypothalamo-pituitary axis, serving as the site of release of hypothalamic neurohormones into a plexus of hypophyseal capillaries. The growth of hypothalamic axons and capillaries to the forming neurohypophysis in embryogenesis is therefore crucial to future adult homeostasis. Using ex vivo analyses in chick and in vivo analyses in mutant and transgenic zebrafish, we show that Fgf10 and Fgf3 secreted from the forming neurohypophysis exert direct guidance effects on hypothalamic neurosecretory axons. Simultaneously, they promote hypophyseal vascularisation, exerting early direct effects on endothelial cells that are subsequently complemented by indirect effects. Together, our studies suggest a model for the integrated neurohemal wiring of the hypothalamo-neurohypophyseal axis.

Pituitary melanotrope cells of Xenopus laevis are of neural ridge origin and do not require induction by the infundibulum.

Classical studies in amphibians have concluded that the endocrine pituitary and pars intermedia are derived from epithelial buccal epidermis and do not require the infundibulum for their induction. These studies also assumed that the pituitary is not subsequently determined by infundibular induction. Our extirpation, auto-transplantation and immunohistochemical studies with Xenopus laevis were initiated to investigate early presumptive pituitary development. These studies were conducted especially with reference to the pars intermedia melanotrope cell's induction, and its production and release of α-melanophore stimulating hormone (α-MSH) from the precursor protein proopiomelanocortin (POMC). Auto-transplantation studies demonstrated that the pituitary POMC-producing cells are determined at a stage prior to pituitary-infundibular contact. The results of experiments involving the extirpation of the presumptive infundibulum also indicated that the infundibulum is not essential for the differentiation of POMC-producing cells. We also demonstrated that early pituitary development involves adherence to the prechiasmatic area of the diencephalon with the pituitary placode growing in a posterior direction toward the infundibulum where contact occurs at Xenopus stage 39/40. Overall, our studies provide a model for early tissue relations among presumptive pituitary, suprachiasmatic nucleus, pars tuberalis and infundibulum during neurulation and later neural tube stages of development. It is hypothesized that the overlying chiasmatic area suppresses pituitary differentiation.

Embryonic morphogenesis of the human pituitary.

Light microscopy methods were used to study the main stages in the organogenesis of the pituitary in human embryos at Carnegie stages (CS) 12-23. Rathke's pouch (RP) was shown to form as a traction fold over whole width of the roof of the stomodeum in embryos at CS 12 due to a flexure of the neural tube with which the epithelium had a tight anatomical relationship (the attached part of the anterior wall of the RP) in the median plane of the embryo. The rudiment of the hypothalamic infundibulum and neurohypophysis formed at CS 15, as a thickening of the posterior wall of the diencephalon. Transorientation of the positions of brain components, including the rudiment of the hypophysis, occurred at CS 20-23. The attached part of the anterior wall of the RP then formed the pars intermedia and pars tuberalis of the anterior lobe, while the epithelium of the orifice of the RP and its posterior wall formed the pars distalis. From CS 20 to 23, the RP epithelium formed the structural-functional units of the adenohypophysis, i.e., the epithelial cords, by invagination.

Involvement of pro-apoptotic and anti-apoptotic factors in the early development of the human pituitary gland.

The spatial and temporal pattern of appearance of pro-apoptotic caspase-3 and p53 proteins, and anti-apoptotic bcl-2 protein was investigated in the developing pituitary gland of 6 human embryos 5-8-weeks old, using morphological and immunohistochemical techniques. Their dynamic appearance was analyzed in the Rathke's pouch (future adenohypophysis), mesenchyme, and in the developing neurohypophysis. In the 5th and 6th week, caspase-3 positive cells appeared in the Rathke's pouch (5%) and stalk (11%), in the mesenchyme, but not in the neurohypophysis. In the 6th and 7th week, apoptotic cells were more numerous in the caudal part of the Rathke's pouch due to its separation from the oral epithelium. Pro-apoptotic p53 protein was detected in all parts of the pituitary gland throughout the investigated period. Nuclear condensations characterized cells positive to caspase-3 and p53 proteins. Apoptotic cells displayed condensations of nuclear chromatin on an ultrastructural level as well. While caspase-3 dependent pathway of cell death participated in morphogenesis of the adenohypophysis and associated connective tissue, p53-mediated apoptosis most likely participates in morphogenesis of all parts of the gland, including neurohypophysis. The anti-apoptotic bcl-2 protein was also detected in all parts of the developing gland. With advancing development, the positivity to bcl-2 protein increased in the cells of the adenohypophysis, while it decreased in the neurohypophysis. Bcl-2 protein probably prevented cell death in all parts of the gland and enhanced cell differentiation. The described pattern of appearance of the investigated pro-apoptotic and anti-apoptotic factors might be important for normal morphogenesis and function of the pituitary gland.

Molecular genetics of pituitary development in zebrafish.

The pituitary gland of vertebrates consists of two major parts, the neurohypophysis (NH) and the adenohypophysis (AH). As a central part of the hypothalamo-hypophyseal system (HHS), it constitutes a functional link between the nervous and the endocrine system to regulate basic body functions, such as growth, metabolism and reproduction. The development of the AH has been intensively studied in mouse, serving as a model for organogenesis and differential cell specification. However, given that the AH is a relatively recent evolutionary advance of the chordate phylum, it is also interesting to understand its development in lower chordate systems. In recent years, the zebrafish has emerged as a powerful lower vertebrate system for developmental studies, being amenable for large-scale genetic approaches, embryological manipulations, and in vivo imaging. Here, we present an overview of current knowledge of the mechanisms and genetic control of pituitary formation during zebrafish development. First, we describe the components of the zebrafish HHS, and the different pituitary cell types and hormones, followed by a description of the different steps of normal pituitary development. The central part of the review deals with the genes found to be essential for zebrafish AH development, accompanied by a description of the corresponding mutant phenotypes. Finally, we discuss future directions, with particular focus on evolutionary aspects, and some novel functional aspects with growing medical and social relevance.

Early development of the pituitary gland in Acipenser naccarii (Chondrostei, Acipenseriformes): an immunocytochemical study.

The distribution and appearance of secretory cells in the pituitary gland were investigated for the first time in a chondrostean species, Acipenser naccarii, from embryos to juveniles, by immunohistochemistry with mammalian and teleost hormone antisera. On 5.5 day post-fertilization (2.5 days pre-hatching), the pituitary of embryos appears as an oval cell mass with a narrow central cavity (hypophysial cleft), close to the ventral border of diencephalon under the third ventricle. At that time no neurohypophysis is observed, the adenohypophysis is not yet structurally divided into pars intermedia (PI) and pars distalis (PD) and only immunoreactive growth hormone cells are detectable. Seven days post-fertilization (1 day pre-hatching) the immunoreactive thyrotropic cells appear in the ventral region and the immunoreactive adrenocorticotropic cells in the posterior dorsal one. At hatching, some immunoreactive melanotropic (ir-MSH) cells are visible in the posterior dorsal region and some immunoreactive prolactin cells in the anterior one. Eight days later the immunoreactive somatolactin cells appear along the posterior dorsal border and the immunoreactive gonadotropic I (ir-GtH I) cells in the ventral region. Here, a few ir-GtH II cells finally appear in 76-86 day old juveniles. The gland elongates after hatching and in 8-day-old larvae two adenohypophysial regions are identified: a posterior (the presumptive PI) and an anterior one (the presumptive PD). In 156-166-day-old juveniles three regions (rostral and proximal pars distalis and pars intermedia) appear and a high number of ir-MSH cells are visible in the rostral region. The first protrusion of neurohypophysis into adenohypophysis is observed in 76-86-day-old juveniles and increases with age, branching into PI. The rostro-caudal distribution of the immunoreactive cells follows the spatial expression of the corresponding hormone gene families observed in zebra fish, suggesting similar differentiating mechanisms in teleosts and chondrosteans.

Immunohistochemical localisation of epidermal growth factor, transforming growth factor alpha and EGF receptor during organogenesis of the murine hypophysis in vivo.

In previous study of melanocyte-stimulating hormone (MSH) cell development in the proliferating pars intermedia, which is in close apposition to the presumptive pars nervosa, no direct cell-to-cell contact was found between the boundary neurohypophyseal pituicytes (PIC), adenohypophyseal precursor stem cells (PSC) and the related diencephalic mesenchymal cells. Here, we have used immunohistochemistry to examine cytokine expression in the development of the hypophysis during foetal stages II-IV. Light and confocal laser scanning microscopy indicated diffuse expression of both TGF alpha and EGF in the hypophysis at different foetal stages. While no findings indicative for temporary changes of TGF alpha and EGF patterns were found in the foetal hypophysis, a temporary increment of EGF molecules was distinct in the diencephalic mesenchyme at stages III and IV. On the other hand, light microscopy intensively immuno-localized EGFR in the adenohypophysis and neurohypophysis at different developmental stages. Immunoreactivity of EGFR in the cytoplasm and nucleus suggested active proliferative events in the PIC and PSC of stages II-IV mouse pituitaries.

Adrenocorticotropin secretion by fetal sheep anterior and intermediate lobe pituitary cells in vitro: effects of gestation and adrenalectomy.

Immunoreactive (ir) ACTH is present in the fetal sheep intermediate lobe (IL) as well as the anterior pituitary (AP). It is not clear whether fetal IL cells can secrete irACTH and if gestational age and glucocorticoids influence the secretion of ACTH from these tissues in a similar fashion. Therefore, we examined the control of irACTH secretion by IL cells, whether the responsiveness of AP and IL cells to arginine vasopressin (AVP) and CRH changes during gestation, and whether withdrawal of adrenal steroids by adrenalectomy influences AP and IL responses. Cultured pituitary cells were studied from intact fetuses at an immature (n = 5; 108 +/- 5 days) and a mature (n = 8; 139 +/- 0 days) stage, from mature fetuses 3 weeks after bilateral adrenalectomy (n = 6), and from neonatal lambs within 16 h of birth (n = 6). Secretion of irACTH was determined by RIA of incubation medium obtained during 3-h exposure of cells to vehicle, AVP, CRH, or both. In all cases, IL cells secreted measurable irACTH. The IL cells of immature fetuses responded to CRH (133 +/- 8% increase over basal secretion), AVP (52 +/- 6%), and CRH plus AVP (244 +/- 8%). In contrast, IL cells from mature fetuses responded only to CRH (160 +/- 20%) or CRH plus AVP (259 +/- 44%), as did cells from mature adrenalectomized fetuses (CRH, 356 +/- 70%; CRH plus AVP, 627 +/- 100%). Secretion from neonatal IL cells was not significantly increased above basal rates by CRH and/or AVP. The AP cells from immature fetuses responded significantly to CRH (406 +/- 16%), AVP (114 +/- 8%), and CRH plus AVP (559 +/- 38%), whereas cells from mature fetuses responded only to AVP (249 +/- 40%) or to CRH plus AVP (570 +/- 146%). In AP cells from mature adrenalectomized fetuses, the response pattern resembled that of immature intact fetal sheep (CRH, 429 +/- 76%; AVP, 146 +/- 15%; CRH plus AVP, 541 +/- 94%). Neonatal AP cells responded to CRH (196 +/- 25%), AVP (442 +/- 71%), and CRH plus AVP (646 +/- 93%). Further characterization of IL cells (n = 6 fetal and 2 neonatal) indicated that they were inhibited by dopamine (basal ACTH secretion decreased by 25 +/- 4%; ACTH secretory response to CRH decreased by 32 +/- 10%). These results show that fetal neurointermediate lobe cells secrete irACTH under basal and stimulated conditions. Moreover, the pattern of response of AP and neurointermediate lobe cells to secretagogues is influenced by gestational age and, possibly, cortisol.

Lipocortin-1 immunoreactivity in the human pituitary gland.

We evaluated the distribution of lipocortin-1 immunoreactivity in 118 immature or mature human hypophyses using the peroxidase-antiperoxidase (PAP) technique with a polyclonal rabbit antiserum against lipocortin-1. Serial sections were evaluated for five pituitary hormones and S-100 protein immunoreactivity to compare their distributions with that of lipocortin-1. Scattered or moderate numbers of cells exhibited lipocortin-1 immunoreactivity in the pars distalis of 89 subjects ranging in age from 27 weeks' gestation to 83 years. Seven immature and seven aged specimens exhibited no immunostaining, while 15 specimens from older individuals exhibited only rare immunostaining. Immunostaining did not appear to co-localize selectively with any specific pituitary hormone, although the distribution of immunoreactivity did overlap that of some corticotrophs and was seen in elongated processes of S-100-containing folliculostellate cells. Lipocortin-1 was also found in epithelial cells lining colloid cysts of the residual pars intermedia in 115 of 118 pituitaries ranging in age from 23 weeks' gestation to 83 years. In many intermediate lobe cysts, lipocortin-1 exhibited a pattern of immunoreactivity that partially overlapped the distribution of S-100 protein immunostaining, although the pattern was not identical. Pre-absorption of anti-lipocortin-1 antiserum with lipocortin-1-coupled Sepharose-4B immunoreactivity resulted in loss of immunoreactivity in both lobes. No lipocortin-1 immunoreactivity was seen in the neurohypophysis.

[Contribution of immunocytochemistry to the study of the development of neuroglandular peptidergic systems in the human fetal hypothalamus]. / Apport de l'immunocytochimie à l'étude du développement de systèmes neuroglandulaires peptidergiques dans l'hypothalamus foetal humain.

Immunohistochemistry makes possible the in situ detection of neuropeptides in the cell bodies were they are synthesized, in the fibers that carry them, and in endings. Immunohistochemistry appears necessary to identify and map peptidergic neurons and to study their ontogeny. From 1975, we have carried the immunohistochemical study of several hypothalamic neuronal populations in the human fetus: LH-RH (1976), somatostatin (1977), pro-opiocortin (1978), vasopressin and oxytocin (1979), corticoliberin (1982), somatocrinin (1983), and hypothalamic neurons containing an unidentified peptide (1984). Comparative ontogenetical studies have also been performed in rats.

The unique endocrine milieu of the fetus.

Table II summarizes in tabular form the major features of the fetal endocrine milieu discussed in the foregoing pages. The mammalian fetus develops in an environment where respiration, alimentation, and excretory functions are provided by the placenta. Fetal tissue metabolism is oriented largely to anabolism; body temperature is modulated by maternal metabolism, and fetal tissue thermogenesis is maintained at a basal level. Tissue and organ growth appear to be regulated by growth factors which probably function by autocrine or paracrine mechanisms during most of gestation (72, 146-148). In this milieu conventional endocrine control systems are largely redundant, and other transient systems more appropriate to the intrauterine environment have evolved. We have developed some insights into these systems, but much more information is necessary before we can truly understand this fascinating environment.

The vascular architecture of the developing pituitary-median eminence complex in the rat.

The development of the pituitary gland and its blood vessels is described in rat embryos (gestational day 12 through day 21) injected with India-ink via the umbilical vessels. The vascularization of all components of the pituitary gland develops from the surface network covering the prosencephalic vesicle. However, vascular connections exist between the prospective median eminence and the anterior pituitary gland in the earliest stages examined (day 12) but are not augmented by vessels from the stomatodeal roof until day 13. Primary portal veins appear initially on day 13, the vascularization of the pars distalis is visible on day 15. The "Mantelplexus" covering the floor of the diencephalon is discernible on day 16. Large-caliber portal veins appear immediately before birth, but otherwise there is no significant change in the vascular pattern during the last five days of gestation. The pars intermedia and the median eminence-pituitary stalk region remain avascular throughout embryonic life.

Anatomical observations of the development of the pituitary capsule.

A morphological study on the development of the pituitary capsule is reported, based on serial or step-sections of 56 pituitary glands from human embryos and fetuses ranging in gestational age from 4 to 40 weeks. Formation of the pituitary capsule is preceded at a very early embryonic stage by mesenchymal cell proliferation around Rathke's pouch when it forms the primitive adenohypophysis. The proportionally large adenohypophysis wraps around the neurohypophysis as it grows down from the diencephalon. Therefore, the fibrous capsule around the adenohypophysis represents the whole hypophysis as a membrane district from the dura mater or pia arachnoid membrane. The pituitary capsule appears not be to a derivative of either the dura mater or the pia arachnoid; instead it is a separate covering of the developing Rathke's pouch.

Vasopressin in fetal sheep: a review.

Advance in fetal sheep surgery has allowed investigation of vasopressin physiology at the end of gestation (100 to 140 days). In the fetus of that age, vasopressin is present in the pituitary and in the blood. The hormonal secretion is stimulated by hypotensive and hyperosmolar stimulus. Hypoxemia is also reported as being a potent stimulus of vasopressin secretion and may have an important effect on blood pressure control.

Histogenesis of the pituitary in rainbow trout (Salmo gairdneri) in different ambient salinities with particular reference to the rostral pars distalis.

The pituitary gland is first evident in rainbow trout two weeks before hatching. Differentiation of prolactin and ACTH cells is not marked until 3-4 days after hatching when the follicular arrangement of the prolactin cells become apparent. There is no difference in the time of development of either prolactin or ACTH cells in larvae reared in different ambient salinities despite marked changes in tissue ion and water content. This suggests that prolactin and ACTH do not play the osmo- and iono-regulatory roles in larval rainbow trout that they are considered to play in adult salmonids.