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M Freemark, M Nagano, M Edery and P A Kelly


The expression of mRNA encoding the long and short forms of the prolactin receptor (PRLR) in the fetal rat was examined using the method of reverse transcription-PCR. A 742 bp PCR product encoding the extracellular and transmembrane domains of the PRLR was detected in maternal and fetal liver and in fetal adrenal, kidney, small intestine, pancreas, brain, pituitary, thymus, lung and skin but not in fetal heart. Highest levels of the 742 bp PRLR transcript were detected in fetal adrenal (45·2% of levels in maternal liver), kidney (27·2%), small intestine (21·7%), pancreas (18·3%) and liver (10·8%), and tissue levels of the 742 bp product correlated positively (r=0·92, P<0·01) with the specific binding of the fetal lactogenic hormone rat placental lactogen II (rPL-II). These findings suggest that the PRLR may serve as a physiological binding protein for rPL-II in the rat fetus. There were striking differences in the relative expression of mRNA encoding the long and short forms of the PRLR. The long form of the receptor was expressed in maternal liver and placenta and in all fetal tissues studied except fetal heart. The short form of the receptor was also detected in maternal liver and placenta and fetal adrenal, kidney, small intestine, liver and thymus; in contrast, there was limited expression of the short-form of the receptor in fetal pancreas, pituitary and brain and no short form transcripts were detected in fetal lung, skin or heart. The results of these studies indicate widespread expression of the rat PRLR in fetal and uteroplacental tissues, implicating diverse roles for the placental prolactin-like proteins in fetal development.

Journal of Endocrinology (1995) 144, 285–292

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Castration of rats on the day of birth abolished the capacity to ejaculate and reduced the capacity to show intromissions in response to testosterone propionate (TP) treatment in adults. Day 10 castrated rats treated daily with oil or day 0 castrated rats treated daily with testosterone benzoate (TB) during the first 10 days of life achieved intromissions and ejaculation after TP treatment in adulthood. Treatment of day 0 castrated rats with a high dose of TB during the first 10 days of life enhanced their capacity to ejaculate in response to TP treatment in adulthood to a level above that of day 10 castrated rats given oil in infancy and similarly treated with TP as adults.

Castration on the day of birth greatly reduced the increase in penis weight and the development of cornified papillae on the glans penis which were seen in day 10 castrated rats after TP treatment in adulthood. These peripheral effects of neonatal testicular secretions are reversed by neonatal treatment of day 0 castrated rats with TB.

Daily treatment of day 0 castrated rats with dihydrotestosterone benzoate (DHTB) during the first 10 days of life facilitated the increase in weight of the penis and the development of cornified papillae on the glans penis but did not enhance the capacity to ejaculate in response to TP treatment in adulthood. Daily treatment of day 0 castrated rats with oestradiol benzoate (OB) during the first 10 days of life facilitated ejaculation without increasing penis sensitivity to TP in adulthood. Combined treatment of the neonate with OB and DHTB was no more effective in facilitating ejaculation in the adult than was OB alone. Neonatal treatment with OB was considerably more potent than neonatal treatment with TB in enhancing ejaculatory behaviour in adulthood.

It is suggested that both the inhibition of the development of lordosis behaviour and the facilitation of the development of mounting behaviour by testicular secretions in newborn rats may be dependent upon, but variously sensitive to, the amount of oestradiol formed in the brain from testosterone in the blood during the first 10 days of life.

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T Walther and H Stepan

C-type natriuretic peptide (CNP) belongs to the natriuretic peptide family that consists of three structurally related peptides with a 17-amino acid ring linked by a disulfide bond. In contrast to atrial and brain natriuretic peptides that are mainly cardiovascular hormones, CNP acts predominantly in an autocrine/paracrine fashion, is commonly considered to be an endothelial hormone with antimitogenic properties, and is characterized as a regulator of endochondral ossification. Its biological effects are mediated by an intracellular cGMP accumulation via specific membrane-bound guanylyl cyclase B (GC-B) activation. There is growing evidence that this peptide is also involved in various reproductive processes as well as in embryonic and fetal development. In rodents, CNP and its receptor are highly expressed in the uterus and ovaries with specific regulation during the estrous cycle. During pregnancy, CNP mRNA is detectable in mice embryos and shows an organ-specific expression in maternal reproductive tIssues with the highest concentration in the placenta. This could indicate a defined biological function of the CNP/GC-B/cGMP axis in gestation e.g. antagonizing vasoconstrictive peptides like angiotensin II. In humans, besides a postulated fetal de novo synthesis of CNP, both the peptide and its receptor are expressed in the placenta and myometrium with opposite regulation of CNP in pregnancies complicated by pre-eclampsia or intrauterine growth retardation. Since the maternal plasma levels do not reflect these alterations, one can conclude that this part of the natriuretic peptide system acts locally suggesting that CNP-stimulated cGMP release exhibits organ-specific effects. Importantly, CNP has also become a peptide with a distinct role in male reproductive processes, since endocrine function of the testis and the regulation of penile erection are regulated by the CNP/GC-B axis. This review gives a comprehensive overview of the multiple functions of CNP in reproduction and pregnancy as well as in embryonic and fetal development.

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HJ Speirs, Seckl JR and RW Brown

Glucocorticoids play important roles in organ development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed ontogeny in the mouse of the glucocorticoid receptor (GR) and 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), which amplifies glucocorticoid levels locally; the ontogeny was determined using in situ hybridisation from embryonic day 9.5 (E9.5, term=E19) until after birth. At E9.5 fetal GR mRNA levels are very low, except in fetal placenta. GR gene expression rises during gestation with striking tissue-specific differences in timing and extent. Before E13.5, an increase is clear in gastrointestinal (GI) and upper respiratory tracts, discrete central nervous system (CNS) regions, precartilage and especially in the liver (E10.5-E12). Later, further increases occur in lung, GI and upper respiratory tracts, muscle, pituitary and thymus. In a few tissues such increases are temporary, e.g. ureteric ducts (E13.5-E16.5) and pancreas (E14.5-E16.5, expression later falling sharply). Fetal 11beta-HSD1 mRNA expression is first clearly observed at E14.5-E15, initially in the fetal placenta then in the umbilical cord. Later, 11beta-HSD1 expression is seen as follows: (i) from E15 in lung and liver, rising strongly; (ii) thymus, from E15 (lower level); (iii) at low levels in a few brain regions, including the hippocampus (E16.5+); and (iv) in muscle group fascial planes and tendon insertions. This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11beta-HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems.

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N. Torres, M. Fanelli, A. L. Alvarez, D. Santajuliana, S. Finkielman and C. J. Pirola


Betamethasone was administered on alternate days to rats, and the role of the central cholinergic system in the development of hypertension assessed. After 15 days of treatment the systolic blood pressure of treated rats was significantly higher than that of control rats. Peripheral administration of atropine but not of methyl atropine reduced systolic pressure in glucocorticoid-treated rats and had no effect in controls. Therefore, [3H]quinuclidinyl benzylate binding, sodium-dependent high-affinity choline uptake and choline acetyltransferase studies were performed in the septal area, anteroventrolateral medulla (AVLM), anterior hypothalamic preoptic area (AH/PO) and hypothalamus. The density of muscarinic receptors was increased in the hypothalamus and AVLM of treated rats without significant changes in affinity. Choline acetyltransferase activity significantly decreased in the AVLM and increased in the AH/PO. In addition, a decrease in the hypothalamus and an increase in the AH/PO of sodium-dependent high-affinity choline uptake was observed in glucocorticoid-treated rats. These results suggest the presence of an enhanced muscarinic cholinergic activity in several brain nuclei in rats with glucocorticoid-induced hypertension. This activation could be due to pre- and post-synaptic hypersensitivity.

Journal of Endocrinology (1991) 129, 269–274

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C Clapp, FJ Lopez-Gomez, G Nava, A Corbacho, L Torner, Y Macotela, Z Duenas, A Ochoa, G Noris, E Acosta, E Garay and G Martinez de la Escalera

Formation of new capillary blood vessels, termed angiogenesis, is essential for the growth and development of tissues and underlies a variety of diseases including tumor growth. Members of the prolactin hormonal family bind to endothelial cell receptors and have direct effects on cell proliferation, migration and tube formation. Because many angiogenic and antiangiogenic factors are produced by endothelial cells, we investigated whether endothelial cells expressed the prolactin gene. Here we show that bovine brain capillary endothelial cells (BBCEC) in culture express the full-length prolactin messenger RNA, in addition to a novel prolactin transcript, lacking the third exon of the gene. In addition cultures of BBCEC synthesize and secrete prolactin-like immunoreactive proteins with apparent molecular masses of 23, 21 and 14 kDa. The prolactin-like nature of these proteins in supported by the observation that Nb2-cells, a prolactin-responsive cell line, were stimulated to proliferate when co-cultured with endothelial cells and this stimulation was neutralized with prolactin-directed antibodies. Finally, consistent with a possible autocrine effect of endothelial-derived prolactins, polyclonal and monoclonal prolactin antibodies specifically inhibited basal and basis fibroblast growth-factor-stimulated growth of endothelial cells. Taken together, the present findings support the hypothesis of the prolactin gene being expressed in endothelial cells as proteins that could act in an autocrine fashion to regulate cell proliferation.

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Male rats were treated daily with 100 μg of the anti-oestrogen ethamoxytriphetol (MER-25) or oil during the first 10 days of life and tested for lordosis behaviour and mounting behaviour as intact adults, after castration and after castration and oestradiol benzoate or testosterone propionate treatment. The MER-25-treated rats showed higher levels of lordosis behaviour than oil-treated rats in all four treatment groups. Under each of these endocrine conditions, except after castration alone, the MER-25-treated rats showed a reduced capacity to ejaculate. Treatment of the neonatal rat with MER-25 reduced body weight in adulthood but did not change the weight of the accessory sexual glands, the testes, the number of cornified papillae on the glans penis or plasma testosterone concentrations during development. The response of the accessory sexual glands and cornified papillae on the glans penis to treatment with oestradiol benzoate or testosterone propionate after castration in adulthood was unaffected by treatment with MER-25. It is suggested that formation of oestrogen in the neonatal male rat brain from testosterone in the circulation inhibits the capacity to show lordosis behaviour and facilitates the capacity to ejaculate in response to gonadal hormone treatment in adulthood.

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G Radaelli, M Patruno, L Maccatrozzo and B Funkenstein

The spatial localization of IGF-II protein and mRNA was investigated during larval and postlarval developmental stages of the gilthead sea bream (Sparus aurata) by immunohistochemistry and in situ hybridization, using specific antisera and riboprobes. Steady-state levels of IGF-II mRNA in larvae were determined by Northern blot analysis and were found to be increased. Immunoreactivity towards IGF-II was found in larval skin, muscle, gills, gut, olfactory epithelium and kidney. After metamorphosis, the strongest immunoreactivity was found in red skeletal muscle. Positive reaction with IGF-II antibodies was also found in the olfactory epithelium and in the epithelia of pharynx, oesophagus, stomach and kidney. In the adult, the most intense signal was observed in the red and pink musculature and in heart musculature. Immunostaining was also found in saccus vasculosus, thymus, spleen and ovary. IGF-II mRNA was detected by in situ hybridization in the brain, olfactory epithelium, eye, pharynx, skeletal musculature and liver. The spatial distribution of IGF-II shown in this study is consistent with previous findings on the cellular localization of IGF type 1 receptor in the sea bream and supports a role for IGF-II during development and growth of sea bream. Furthermore, these results suggest that IGF-II acts in an autocrine/paracrine manner.

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1. Purified anterior pituitary growth hormone has been given to pregnant rats and a study made of the cerebral development of the young in terms of behaviour, electrical activity of the brain and the quantitative histology of the cerebral cortex.

2. The experimental treatment resulted in an increase in the size of the young at birth. The maturation of innate and reflex behavioural responses was little affected but the performance of cortically mediated behaviour was enhanced. Little significant change was observed in the electroencephalogram other than an abnormal response to photic stimulation.

3. These physiological effects were associated with a modified pattern of cortical maturation consistent with a hypertrophy of neurones. This was reflected in an enlargement of the perikarya and an expansion of protoplasmic processes resulting in an increase in the statistical probability of interaction between neurones.

4. The results are discussed in relation to the earlier and somewhat dissimilar findings reported by Zamenhof (1942), and are regarded as consistent with previously formulated hypotheses linking the structure of the cerebral cortex with its mode of functioning.

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A. M. Cowell


Over the last decade the role of excitatory amino acids (EAAs) in the central nervous system has been the focus of much research and there is now widespread evidence that EAAs are critical to a number of aspects of brain function, such as long term potentiation and neural degeneration. They exert their effects through a variety of different receptor subtypes which have been classified on the basis of selective agonist and antagonist actions as (1) N-methyl-d-aspartic acid (NMDA) receptors, (2) kainic acid (KA) receptors, (3) 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptors, which were originally named quisqualic acid (QA) receptors because they are also activated by QA, (4) amino-4-phosphobutyric acid (L-AP-4) receptors and (5) metabotropic receptors which are activated by QA and trans-1-amino-cyclopentyl-1,1,3-dicarboxylic acid (Fagg & Masssieu, 1991). These receptors are now regarded as a primary target for drug development for a variety of conditions such as epilepsy,