Growth hormone cell differentiation normally occurs between day 14 and day 16 of chicken embryonic development. We reported previously that corticosterone (CORT) could induce somatotroph differentiation in vitro and in vivo and that thyroid hormones could act in combination with CORT to further augment the abundance of somatotrophs in vitro. The objective of the present study was to test our hypothesis that endogenous thyroid hormones regulate the abundance of somatotrophs during chicken embryonic development. Plasma samples were collected on embryonic day (e) 9-14. We found that plasma CORT and thyroid hormone levels increased progressively in mid-embryogenesis to e 13 or e 14, immediately before normal somatotroph differentiation. Administration of thyroxine (T4) and triiodothyronine (T3) into the albumen of fertile eggs on e 11 increased somatotroph proportions prematurely on e 13 in the developing chick embryos in vivo. Furthermore, administration of methimazole, the thyroid hormone synthesis inhibitor, on e 9 inhibited somatotroph differentiation in vivo, as assessed on e 14; this suppression was completely reversed by T3 replacement on e 11. Since we reported that T3 alone was ineffective in vitro, we interpret these findings to indicate that the effects of treatments in vivo were due to interactions with endogenous glucocorticoids. These results indicate that treatment with exogenous thyroid hormones can modulate somatotroph abundance and that endogenous thyroid hormone synthesis likely contributes to normal somatotroph differentiation.
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S. H. LIU and R. L. NOBLE
Evans, Meyer, and Simpson  reported that in male hypophysectomized rats an extract of pregnant mare serum was capable of causing regeneration of atrophied testes and resumption of spermatogenesis and fertility. The accessory organs grew to normal size. Histologically the testes of the injected animals appeared normal. Similar results have been achieved with extracts of human pregnancy urine by Smith and Leonard  and Evans, Pencharz, and Simpson . In the present experiments the relative efficiency of these two types of gonadotrophic extract have been compared in their ability to maintain and restore the reproductive system of hypophysectomized male rats.
Male albino rats of the Wistar Institute strain, 2½ to 3 months old, weighing 150 to 190 g. were hypophysectomized by a modified Selye technique [Collip, Selye, and Thomson, 1933]. Criteria of complete hypophysectomy were body-weight curve, adrenal weight, and examination of sella turcica at autopsy. In doubtful cases
S. H. LIU and R. L. NOBLE
In a preceding paper [Liu and Noble, 1939] it has been shown that in male hypophysectomized rats, extracts of both pregnant mare serum and pregnancy urine were capable of exerting a marked effect on the testes as well as on the accessory sex organs. In the present experiments it was attempted to determine how far the results obtained on the male were comparable with those on the female hypophysectomized rats under similar experimental conditions.
The experimental procedure was the same as previously reported . Vaginal smears were made daily to determine the oestrogenic activity. In mating experiments, normal males were placed with the hypophysectomized females at 2 weeks after the commencement of treatment.
Hypophysectomized controls. As shown in Table I, the rate of atrophy of ovaries and uteri of hypophysectomized rats was gradual up to 6 weeks after operation. After that time very little further decline in weight
M Candolfi, G Jaita, D Pisera, L Ferrari, C Barcia, C Liu, J Yu, G Liu, M G Castro, and A Seilicovich
Our previous work showed that tumor necrosis factor (TNF)-α and FasL induce apoptosis of anterior pituitary cells. To further analyze the effect of these proapoptotic factors, we infected primary cultures from rat anterior pituitary, GH3 and AtT20 cells with first-generation adenoviral vectors encoding TNF-α, FasL or, as a control, β-galactosidase (β-Gal), under the control of the human cytomegalovirus promoter. Successful expression of the encoded transgenes was determined by immunocytochemistry. Although we observed basal expression of TNF-α and FasL in control cultures of anterior pituitary cells, fluorescence-activated cell sorting (FACS) cell cycle analysis showed that the overexpression of TNF-α or FasL increases the percentage of hypodiploid lactotropes and somatotropes. Nuclear morphology and TUNEL staining revealed that the cells undergo an apoptotic death process. We detected strong immunoreactivity for TNFR1 and Fas in the somatolactotrope cell line GH3. TNF-α, but not FasL, was expressed in control cultures of GH3 cells. The infection of GH3 cells with adenovirus encoding TNF-α or FasL increased the percentages of hypodiploid and TUNEL-positive cells. TNF-α or FasL immunoreactivity was not observed in the corticotrope cell line AtT20. However, adenovirus encoding TNF-α or FasL efficiently transduced these cells and increased the percentages of hypodiploid and TUNEL-positive cells. The expression of β-Gal was detected in all these cultures but did not affect cell viability. In conclusion, these results suggest that death signaling cascades triggered by TNF receptor 1 (TNFR1) and Fas are present in both normal and tumoral pituitary cells. Therefore, overexpression of proapoptotic factors could be a useful tool in the therapy of pituitary adenomas.
C R Liu, L Y Li, F Shi, X Y Zang, Y M Liu, Y Sun, and B H Kan
Thyroid dysfunction is classified into hyperthyroidism and congenital hypothyroidism (CH). Both hyperthyroidism and CH can cause heart lesions; however, the mechanisms involved remain unclear. The left ventricle was collected from eu-, hyper-, and hypothyroid rat. RNA was extracted and reverse-transcripted to cDNA. Real-time fluorescence quantitation-PCR was used to quantify the differential expression of thyroid hormone receptor (TR) subtype mRNA among eu-, hyper-, and hypothyroid rat myocardium. Here, we show that compared with the normal myocardium, TRα1 mRNA expression was upregulated by 51% (P<0.01), TRα2 mRNA expression was downregulated by 58% (P<0.01), and TRβ1 mRNA expression remained unchanged in hyperthyroid rat myocardium (P>0.05). TRα1, TRα2, and TRβ1 were expressed in normal and hypothyroid rat myocardium throughout the developmental process. In hypothyroid rats, myocardial TRα1 mRNA expression was generally downregulated and the expression peak appeared late. Myocardial TRα2 mRNA expression was generally upregulated and the expression peak appeared late. Myocardial TRβ1 mRNA expression was generally downregulated and changed similarly with the control group. In addition, the hypogenetic myocardium can be seen in the hypothyroid rat by pathology study. Taken together, the abnormal expression of TR subtype mRNA may have a close relationship with the pathogenesis of CH and hyperthyroidism heart disease.
G Liu, SV Pakala, D Gu, T Krahl, L Mocnik, and N Sarvetnick
In developmental terms, the endocrine system of neither the gut nor the pancreatic islets has been characterized fully. Little is known about the involvement of cholecystokinin (CCK), a gut hormone, involved in regulating the secretion of pancreatic hormones, and pancreatic growth. Here, we tracked CCK-expressing cells in the intestines and pancreata of normal mice (BALB/c), Non Obese Diabetic (NOD) mice and interferon (IFN)-gamma transgenic mice, which exhibit pancreatic regeneration, during embryonic development, the postnatal period and adulthood. We also questioned whether IFN-gamma influences the expression of CCK. The results from embryonic day 16 showed that all three strains had CCK in the acinar region of pancreata, and specifically in alpha cells that also expressed glucagon. However, in adulthood only BALB/c and NOD mice continued this pattern. By contrast, in IFN-gamma transgenic mice, CCK expression was suppressed from birth to 3 months of age in the pancreata but not intestines. However, by 5 months of age, CCK expression appeared in the regenerating pancreatic ductal region of IFN-gamma transgenic mice. In the intestine, CCK expression persisted from fetus to adulthood and was not influenced by IFN-gamma. Intestinal cells expressing CCK did not co-express glucagon, suggesting that these cells are phenotypically distinct from CCK-expressing cells in the pancreatic islets, and the effect of IFN-gamma on CCK varies depending upon the cytokine's specific microenvironment.
Z H Liu, K Tsuchida, T Matsuzaki, Y L Bao, A Kurisaki, and H Sugino
Activin type II receptors (ActRIIs) including ActRIIA and ActRIIB are serine/threonine kinase receptors that form complexes with type I receptors to transmit intracellular signaling of activins, nodal, myostatin and a subset of bone morphogenetic proteins. ActRIIs are unique among serine/threonine kinase receptors in that they associate with proteins having PSD-95, Discs large and ZO-1 (PDZ) domains. In our previous studies, we reported specific interactions of ActRIIs with two independent PDZ proteins named activin receptor-interacting proteins 1 and 2 (ARIP1 and ARIP2). Overexpression of both ARIP1 and ARIP2 reduce activin-induced transcription. Here, we report the isolation of two isoforms of ARIP2 named ARIP2b and 2c. ARIP2, ARIP2b and ARIP2c recognize COOH-terminal residues of ActRIIA that match a PDZ-binding consensus motif. ARIP2 and its isoforms have one PDZ domain in the NH2-terminal region, and interact with ActRIIA. Although PDZ domains containing GLGF motifs of ARIP2b and 2c are identical to that of ARIP2, their COOH-terminal sequences differ from that of ARIP2. Interestingly, unlike ARIP2, overexpression of ARIP2b or 2c did not affect ActRIIA internalization. ARIP2b/2c inhibit inhibitory actions of ARIP2 on activin signaling. ARIP2 is widely distributed in mouse tissues. ARIP2b/2c is expressed in more restricted tissues such as heart, brain, kidneys and liver. Our results indicate that although both ARIP2 and ARIP2b/2c interact with activin receptors, they regulate ActRIIA function in a different manner.
Shiguang Liu, Peter S N Rowe, Luke Vierthaler, Jianping Zhou, and L Darryl Quarles
Inactivating PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome) mutations cause X-linked hypophosphatemia in humans and mice (Hyp) through overproduction of fibroblast growth factor 23 (FGF23) a phosphaturic factor, by osteocytes. Matrix extracellular phosphoglycoprotein (MEPE) is also elevated in Hyp and other hypophosphatemic disorders. In addition, the administration of an ASARM (acidic serine–aspartate rich MEPE-associated motif) peptide derived from MEPE causes phosphaturia and inhibits bone mineralization in mice, suggesting that MEPE also plays a role in phosphate homeostasis. Since recent studies found that MEPE binds specifically to PHEX in vitro, we tested the effect of recombinant-MEPE and its ASARM peptide on PHEX enzyme activity in vitro and FGF23 expression in bone marrow stromal cell cultures ex vivo. We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO4) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay. The ASARM-PO4 peptide inhibits PHEX enzyme activity in a dose-dependent manner with a K i of 128 nM and V max−i of 100%. Recombinant MEPE also inhibits PHEX activity (K i = 2 nM and V max−i = 26%). Long-term bone marrow stromal cell cultures supplemented with 10 μ M ASARM-PO4 peptide resulted in significant elevation of FGF23 transcripts and inhibition of mineralization. These findings suggest that MEPE inhibits mineralization and PHEX activity and leads to increased FGF23 production. The resulting coordination of mineralization and release of a phosphaturic factor by MEPE may serve a physiological role in regulating systemic phosphate homeostasis to meet the needs for bone mineralization.
Y L Bao, K Tsuchida, B Liu, A Kurisaki, T Matsuzaki, and H Sugino
Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons. However, the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood. In the present study, we report that activin A and basic fibroblast growth factor (bFGF) synergistically increased the protein level of tyrosine hydroxylase (TH), and also greatly increased the TH mRNA level, in both mouse E14 striatal primary cell cultures and the hippocampal neuronal cell line HT22. Activin A and bFGF cooperatively stimulated nuclear translocation of Smad3 and specifically activated ERK1/2, but not p38 or JNK. Interestingly, a specific inhibitor for MEK, U0126, efficiently blocked the induction of TH promoter activity by activin A and bFGF, indicating that activin A collaborated with bFGF signaling to induce the TH gene through selective activation of ERK-type MAP kinase in mouse striatal and HT22 cells. These data suggest that activin A may act in concert with bFGF for the development of TH-positive neurons.
L Yang, CB Kuo, Y Liu, D Coss, X Xu, C Chen, ML Oster-Granite, and AM Walker
During rat pregnancy initial high concentrations of prolactin (PRL) decline by about day 9, concomitant with an increase in the ratio of unmodified to phosphorylated PRL. The physiological significance of both the decline in total PRL and the change in ratio of the two PRLs is unknown. To test the importance of each, either unmodified PRL (U-PRL) or a molecular mimic of phosphorylated PRL (PP-PRL) were continuously administered to rats throughout pregnancy. A dose of 6 microg/24 h resulted in circulating concentrations of 50 ng/ml of each administered PRL and had little effect on the pregnancy itself. After birth, pups were killed and various tissues examined. In the pup lungs, exposure to additional PP-PRL caused a reduction in epithelial integrity and an increase in apoptosis, whereas exposure to additional U-PRL had beneficial, anti-apoptotic effects. In the heart, PP-PRL caused an apparent developmental delay, whereas U-PRL promoted tissue compaction. In the blood, U-PRL increased the number of mature red blood cells at the expense of white blood cell production. Within the white blood cell population, myelopoiesis was favored at the expense of lymphopoiesis. PP-PRL, in contrast, had a less dramatic influence on the hematopoietic compartment by promoting red blood cell maturation and granulocyte production. In the thymus, exposure to PP-PRL caused accumulation of apoptotic thymocytes in enlarged glands, whereas exposure to U-PRL resulted in smaller thymi. In the spleen, exposure to U-PRL increased cellularity, with the majority of cells belonging to the erythroid series - a finding consistent with increased red blood cells in the circulation. Exposure to PP-PRL was without discernible effect. In all of these tissues, the contrasting effects of the two PRLs indicate that the absolute concentration of PRL is not crucial, but that the ratio of U-PRL to PP-PRL has a profound effect on tissue development. In brown fat, both PRL preparations decreased the number of lipid droplets. This result is therefore probably a consequence of the increase in total PRL. The results of this study attest to the importance of the U-PRL:PP-PRL ratio normally present during pregnancy and have provided clues as to the possible pathogenesis of a variety of neonatal problems.