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G Schreiber

In larger mammals, thyroid hormone-binding plasma proteins are albumin, transthyretin (TTR) and thyroxine (T4)-binding globulin. They differ characteristically in affinities and release rates for T4 and triiodothyronine (T3). Together, they form a 'buffering' system counteracting thyroid hormone permeation from aqueous to lipid phases. Evolution led to important differences in the expression pattern of these three proteins in tissues. In adult liver, TTR is only made in eutherians and herbivorous marsupials. During development, it is also made in tadpole and fish liver. More intense TTR synthesis than in liver is found in the choroid plexus of reptilians, birds and mammals, but none in the choroid plexus of amphibians and fish, i.e. species without a neocortex. All brain-made TTR is secreted into the cerebrospinal fluid, where it becomes the major thyroid hormone-binding protein. During ontogeny, the maximum TTR synthesis in the choroid plexus precedes that of the growth rate of the brain and occurs during the period of maximum neuroblast replication. TTR is only one component in a network of factors determining thyroid hormone distribution. This explains why, under laboratory conditions, TTR-knockout mice show no major abnormalities. The ratio of TTR affinity for T4 over affinity for T3 is higher in eutherians than in reptiles and birds. This favors T4 transport from blood to brain providing more substrate for conversion of the biologically less active T4 into the biologically more active T3 by the tissue-specific brain deiodinases. The change in affinity of TTR during evolution involves a shortening and an increase in the hydrophilicity of the N-terminal regions of the TTR subunits. The molecular mechanism for this change is a stepwise shift of the splice site at the intron 1/exon 2 border of the TTR gene. The shift probably results from a sequence of single base mutations. Thus, TTR evolution provides an example for a molecular mechanism of positive Darwinian evolution. The amino acid sequences of fish and amphibian TTRs are very similar to those in mammals, suggesting that substantial TTR evolution occurred before the vertebrate stage. Open reading frames for TTR-like sequences already exist in Caenorhabditis elegans, yeast and Escherichia coli genomes.

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The secretion of growth hormone from anterior pituitary transplants under the kidney capsule of gonadectomized and hypophysectomized male rats was investigated with special regard to the importance of the mass of functioning pituitary tissue. Body growth and mammary gland development after testosterone stimulation were studied.

In rats with the pituitary gland autotransplanted to the kidney capsule body growth was markedly reduced. After administration of testosterone a few groups of alveoli only were seen in the mammary glands.

Hypophysectomized rats with four pituitary transplants (an autotransplant and three homotransplants) under the kidney capsule showed slightly better body growth than rats with an autotransplanted hypophysis. When compared with rats with intact pituitary glands body growth was markedly reduced. Mammary gland development after testosterone stimulation was as poor in rats with four pituitary transplants as in rats with an autotransplanted hypophysis.

These results suggest strongly that the normal secretion of growth hormone is regulated by the hypothalamus and that the deficiency of growth hormone in rats with the pituitary gland transplanted remote from the brain is due mainly to a loss of 'specific' stimuli from the hypothalamus and not to a 'non-specific' reduction in the amount of functioning pituitary tissue.

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BH Min, SY Jeong, SW Kang, BG Crabo, DN Foster, BG Chun, M Bendayan, and IS Park

Clusterin has been known to play important roles not only in remodeling damaged tissues, but also in tissue reorganization during embryonic development. In the present study, we have investigated the expression of clusterin in the endocrine pancreas during embryonic development. Although a weak immunoreaction was detected in some pancreatic primordial cells at day 14 of gestation, distinct clusterin expression was identified by immunocytochemistry and Northern blot analysis at the 16th day of gestation. Clusterin-producing cells, which corresponded to insulin-containing cells, accounted for the major portion of the developing islet of Langerhans up to 18 days of gestation. Thereafter, clusterin-producing cells display similar distribution and morphological features to glucagon-producing cells. Clusterin expressed in the pancreas was shown by Western blot analysis to be a disulfide-linked heterodimer of 70 kDa with an alpha-subunit of 32 kDa. During early developmental stages, however, we found that proteolytic internal cleavage of the clusterin molecule occurred from the 18th day of gestation. Only one 70 kDa band on the 16th day and two bands (32 kDa and 70 kDa) on the 18th day of gestation were detected by Western blot analysis even in reducing conditions, while only a single 32 kDa band was detected on the second day after birth. The levels of clusterin mRNA in the pancreas transiently increased from the 16th day of gestation to the second day after birth, during the period when active cellular reorganization takes place to form the classic cellular features of the islet. Among various tissue (kidney, brain, liver, heart, lung and pancreas) the levels of clusterin mRNA were the highest in the pancreas from the 18th day of gestation to the second day after birth. In contrast, the lowest expression was observed in adult pancreatic tissue. The higher expression of clusterin in developing pancreas must indicate its involvement in tissue organization during development.

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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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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,

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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.