The somatomedins or insulin-like growth factors (IGFs) are synthesized in many organs and tissues, but the specific cells that synthesize them in vivo have not been defined. By in situ hybridization histochemistry, IGF I (somatomedin C) and IGF II messenger RNAs were localized to connective tissues or cells of mesenchymal origin in 14 organs and tissues from human fetuses. IGF messenger RNAs were localized to perisinusoidal cells of liver, to perichondrium of cartilage, to sclera of eye, and to connective tissue layers, sheaths, septa, and capsules of each organ and tissue. All of the hybridizing regions are comprised predominantly of fibroblasts or other cells of mesenchymal origin. Because these cells are widely distributed and anatomically integrated into tissues and organs, they are ideally located for production of IGFs, which may exert paracrine effects on nearby target cells.

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LCoR (ligand-dependent corepressor) is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LXXLL motif. LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2. Repression by LCoR is abolished by histone deacetylase inhibitor trichostatin A in a receptor-dependent fashion, indicating HDAC-dependent and -independent modes of action. LCoR binds directly to specific HDACs in vitro and in vivo. Moreover, LCoR functions by recruiting C-terminal binding protein corepressors through two consensus binding motifs and colocalizes with CtBPs in the nucleus. LCoR represents a class of corepressor that attenuates agonist-activated nuclear receptor signaling by multiple mechanisms.

Although glucagonlike immunoreactants (GLIs) are present in the central nervous system of several mammalian species, their structural relationship with pancreatic proglucagon is not defined, and their precise anatomical distribution has not been studied extensively. To obtain further information about the structure and biological significance of brain GLIs, the anatomical distribution of three different antigenic determinants of pancreatic proglucagon--glucagonlike peptide I (GLP-I), glucagon, and glicentin--was mapped in the brain of colchicine-treated rats by immunocytochemistry using the avidin-biotin-peroxidase method. Neuronal cell bodies immunoreactive with antisera specific for GLP-I, glucagon, and glicentin were found only in the caudal medulla oblongata. Within the caudal medulla immunostained cell bodies were found at levels from approximately 0.55 mm rostral to the obex to 0.45 mm caudal to the obex, and were located within the nucleus of the solitary tract (NTS) and the dorsal (MdD) and ventral (MdV) parts of the medullary reticular nucleus. The NTS contained three times more immunoreactive cell bodies than the MdD and MdV, and these cell bodies were located in the midline, medial, and lateral subnuclei of the caudal third of the NTS. Immunostaining of the same cell bodies in paired adjacent sections incubated with GLP-I and glucagon antisera or glucagon and glicentin antisera provided evidence for coexistence of the three antigens within the same neurons of the NTS. Nerve fibers and terminals immunoreactive with GLP-I, glucagon, and glicentin antisera were widely distributed throughout the rat brain and there was no discernible difference in the distribution of fibers and terminals immunoreactive with each of the three antisera. The highest densities of immunostained fibers and terminals were observed in the hypothalamus, thalamus, and septal regions, and the lowest in the cortex and hindbrain. The localization of neuronal cell bodies containing GLP-I, glucagon, and glicentin within the NTS and the MdD and MdV, and the extensive distribution of immunoreactive fibers and terminals throughout the rat brain suggest a role for these peptides in the integration of autonomic as well as central nervous system functions.

Several lines of evidence indicate that multiple human fetal tissues synthesize somatomedins/insulin-like growth factors (Sm/IGFs). To investigate the synthesis of Sm/IGFs in vivo, we isolated polyadenylated RNAs from multiple human fetal tissues of 16-20 weeks gestation and performed Northern and dot-blot analyses using 32P-labeled cDNAs and oligodeoxyribonucleotide (oligomer) probes complementary to human Sm-C/IGF-I and IGF-II mRNAs. Sm-C/IGF-I mRNAs were present in all tissues studied. IGF-II mRNAs were detectable in all tissues except the cerebral cortex and hypothalamus. IGF-II mRNA levels were consistently higher than Sm-C/IGF-I mRNAs in all tissues where IGF-II mRNAs were detectable (varying from 2-fold higher in spleen and thymus to 650-fold higher in liver), suggesting that IGF-II is synthesized in greater quantities than Sm-C/IGF-I in most tissues during early fetal life. Liver, adrenal, and skeletal muscle had the highest levels of IGF-II mRNAs, while placenta and stomach had the highest level of Sm-C/IGF-I mRNAs. Multiple Sm-C/IGF-I and IGF-II transcripts were identified with estimated sizes 0.7, 5.3, and 8.0 kilobases (kb) for Sm-C/IGF-I and 1.8, 2.0, 2.8, 3.0, 4.0, 4.8, and 6.2 kb for IGF-II. The 5.3-kb species was the most abundant Sm-C/IGF-I mRNA. The largest Sm-C/IGF-I transcript (8.0 kb) was identified in the intestine, muscle, kidney, placenta, stomach, heart, skin, pancreas, hypothalamus, and brain stem and was most abundant in the hypothalamus and muscle. The smallest transcript (0.7 kb) was detectable only in spleen, adrenal, placenta, and stomach. On the other hand, nearly all species of IGF-II mRNAs were found in tissues with detectable mRNAs, with the 6.2-kb mRNA being the most abundant. The variation in abundance and species of Sm-C/IGF-I and IGF-II mRNAs among different human fetal tissues suggests tissue-specific differences in Sm-C/IGF-I and IGF-II gene expression, mRNA precursor processing, and/or mRNA stability. Such differences may have significance for the roles of Sm-C/IGF-I and IGF-II during human fetal development. The finding of Sm/IGF mRNAs in many human fetal tissues also supports a local role for Sm/IGFs in human fetal development.

The placenta synthesizes insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), which are believed to regulate its growth and development in an autocrine/paracrine manner. To delineate the cellular sites of expression of IGP and IGFBP messenger ribonucleic acids (mRNAs) in human placenta throughout pregnancy, we used in situ hybridization histochemistry with 35S-labeled IGF and IGFBP complementary RNA probes on human placentas and fetal membranes of gestational ages 6 weeks to term (40 weeks). In placental regions where trophoblasts (fetal) or decidua (maternal) coexist (e.g. basal plate), the identity was delineated by their cytokeratin or vimentin immunoreactivity, respectively. Except for IGF-II, mRNAs encoding peptides of the IGF system were expressed in a similar spatial pattern and relative abundance throughout gestation. Both IGF mRNAs showed similar tissue distribution, but the IGF-II mRNA was more abundant than IGF-I mRNA at all gestational ages. IGF-II mRNA was expressed in the chorionic mesoderm of placental villi and chorionic plate in moderate abundance, and it decreased with gestation. It was also expressed in the trophoblasts of the cytotrophoblastic shell and Langhan's layer of placental villi only in the first trimester, suggesting an autocrine role for IGF-II in early cytotrophoblastic proliferation and/or differentiation. IGF-II mRNA was expressed most abundantly in the columns of intermediate trophoblasts in the anchoring villi and chorionic and basal plates. A gradient of IGF-II mRNA abundance was observed in the trophoblasts of the cytotrophoblastic column, with greater IGF-II mRNA levels in those at the invading front, suggesting a role for IGF-II in trophoblastic invasion. In the fetal membranes, IGF-II mRNA was identified in the amnion and chorion laeve. IGF-I receptor mRNA was expressed in low abundance in all cell types of the placenta. All six IGFBP mRNAs were identified in variable abundance in the decidualized stromal cells of the maternal decidua basalis and parietalis, with IGFBP-1 mRNA being expressed in the greatest abundance. The spatial pattern of expression of each IGFBP mRNA also differed among decidual cells, with IGFBP-1, IGFBP-2, IGFBP-4, and IGFBP-6 mRNAs being expressed in most cells, whereas IGFBP-3 and IGFBP-5 mRNAs were expressed in only some cells. IGFBP-1 mRNA was expressed initially in the epithelium of endometrial glands and in a population of decidualized stromal cells in early gestation, and subsequently in the majority of decidualized stromal cells. IGFBP-3 mRNA was expressed in both the decidua and certain intermediate trophoblasts of the basal plate and anchoring villi of placenta and in amnion and chorion laeve of fetal membranes. IGFBP-4 and IGFBP-5 mRNA were expressed additionally in low abundance in the chorionic mesoderm. IGFBP-6 was expressed in greater abundance in the decidua parietalis than in decidua basalis, although the general level of expression was low. The spatial pattern and relative abundance of expression of IGFBP mRNAs sug...

The placenta synthesizes insulin

Our aim was to determine the effect of short-term (7 days) alterations in fetal lung liquid volume on pulmonary DNA synthesis rates and insulin-like growth factor-II (IGF-II) mRNA levels. Fifteen chronically catheterized fetal sheep were divided into three groups. In one, the trachea was obstructed, in another lung liquid was drained by gravity, and the third group served as controls. After 7 days, [3H]thymidine was injected into each fetus and 8 h later fetal tissues were collected. Fetal lung-to-body weight ratios and total lung DNA contents were greatly increased in fetuses with tracheal obstruction compared with control fetuses, whereas the drainage of lung liquid did not affect these measurements. DNA synthesis rates in pulmonary tissue were significantly reduced from a mean control value of 153.3 +/- 25.1 disintegrations per minute (dpm)/microgram DNA to 57.2 +/- 8.6 dpm/microgram DNA by lung liquid drainage (P < 0.05) and were significantly increased to 236.0 +/- 24.0 dpm/microgram DNA by tracheal obstruction (P < 0.05). Following tracheal obstruction, lung IGF-II mRNA levels were increased to 177.0 +/- 18.2% (P < 0.05) of the mean value for control fetuses, whereas they were reduced to 56.1 +/- 7.1% of control in lung liquid-drained fetuses. We conclude that altering fetal lung expansion has a potent and rapid effect on pulmonary DNA synthesis and that this effect may, in part, be mediated by an alteration in IGF-II gene expression.