Insulin-Like Growth Factor-I Promotes Neurogenesis and Synaptogenesis in the Hippocampal Dentate Gyrus during Postnatal Development

Th

Rat astroglial somatomedin/insulin-like growth factor binding proteins: characterization and evidence of biologic function

Specific binding proteins (BPs) to somatomedin/insulin-like growth factors (Sm/IGFs) have been identified in conditioned media from a variety of cells in culture. By affinity cross-linking using disuccinimidyl suberate, we have covalently cross-linked radiolabeled somatomedin-C/insulin-like growth factor I (Sm-C/IGF I), insulin-like growth factor II (IGF II) and insulin to BPs in conditioned medium (CM) from cultured astroglial cells derived from cerebral cortices of neonatal rats. Two species of radiolabeled Sm/IGF BP complexes of 40,000 Da (40K) and 45K were identified. Competition with unlabeled Sm- C/IGF I and IGF II demonstrated that the BPs in each complex have similar affinities for Sm-C/IGF I and IGF II. The BP in the 45K complex was about 5-fold more sensitive to competition with unlabeled Sm/IGFs than the BP in the 40K complex, suggesting that it either has a higher affinity for Sm/IGFs or is less abundant. Evidence that the BPs in each complex are distinct includes the following findings: (1) insulin competed with Sm/IGF for binding to the 45K complex, but not the 40K complex, and (2) the BP in the 40K complex, but not the 45K complex, was recognized by antibodies raised against a BP purified from CM of buffalo rat liver (BRL) 3A cells. Growth hormone did not affect the apparent secretion of either BP. The binding activity of both BPs was retained after mild heat treatment, changes to extremes of pH (2–10), and prolonged storage at -20 degrees C, but was destroyed after heating to higher temperatures (80 degrees C and greater), reduction, and proteolytic treatment.(ABSTRACT TRUNCATED AT 250 WORDS

Characterization of somatomedin/insulin-like growth factor receptors and correlation with biologic action in cultured neonatal rat astroglial cells

The role of somatomedin/insulin-like growth factors (Sm/IGFs) in neural growth and development is not clearly defined. To characterize Sm/IGF receptors and to correlate binding with the biologic actions of Sm/IGFs in a homogeneous population of neural cells, we isolated and studied a nearly pure population of cultured astroglial monolayers derived from cerebral cortices of neonatal rats. Binding of radiolabeled Sm/IGFs was specific, saturable, and reversible, with 90% of the binding occurring within 6 hr of incubation at 4 degrees C. Competitive binding studies with Sm-C/IGF I yielded curvilinear Scatchard plots, while studies with IGF II and multiplication stimulating activity (MSA) yielded linear plots, suggesting that 125I-Sm-C/IGF I binds to more than 1 receptor species, and 125I-IGF II and 125I-MSA bind to one only. These findings were supported by affinity-labeling studies with radiolabeled Sm/IGFs using disuccinimidyl suberate as a cross-linking agent. Sm-C/IGF I appeared to bind to both type I and II Sm/IGF receptors, because cross- linked 125I-Sm-C/IGF I-receptor complexes with molecular weight (Mr) of greater than 300,000 (300K) and 130K (type I receptor) were observed under nonreducing and reducing conditions, respectively, as were 220 and 260K complexes (type II receptor) under the same respective conditions. 125I-IGF II and 125I-MSA, however, bound only to the Mr 220 and 260K moieties under nonreducing and reducing conditions, respectively, suggesting that these peptides bind only to the type II receptor. Competitive binding studies of the cross-linked moieties were consistent with this interpretation. In contrast, 125I-insulin bound poorly to astroglia (less than 0.5% specific binding), and cross- linking studies could not definitely distinguish among low-affinity binding to the type I Sm/IGF receptor, binding to a paucity of insulin receptors, or both. In addition, by combining autoradiography to localize 125I-Sm/IGFs binding on astroglial cells and immunocytochemistry with anti-glial fibrillary acidic protein to identify the cell type, we have demonstrated cell-surface binding and apparent internalization of radiolabeled Sm/IGFs. Concurrent studies of Sm/IGF stimulation of 3H-thymidine incorporation revealed that these cells were most sensitive to Sm-C/IGF I, followed by IGF II and MSA, and insulin. MSA and IGF II, however, were the most potent followed by Sm-C/IGF I and then insulin. Half-maximal stimulations of 3H-thymidine incorporation corresponded closely with half-maximal binding displacement for Sm-C/IGF I and less so for IGF II and MSA.(ABSTRACT TRUNCATED AT 400 WORDS

Interaction of secreted insulin-like growth factor-I (IGF-I) with cell surface receptors is the dominant mechanism of IGF-I's autocrine actions

In a prior report we presented evidence that insulin-like growth factor-I (IGF-I) can act in an autocrine fashion by demonstrating that FRTL-5 cells transfected with hIGF-IA fusion genes express and secrete biologically active IGF-I that renders the stimulation of DNA synthesis in FRTL-5 cells independent of their requirement for exogenous IGFs or insulin. To determine if IGF-I's autocrine actions require secretion or can be mediated by interactions with intracellular receptors, we have created a new line of FRTL-5 cells that express a mutant IGF-IA precursor containing the endoplasmic reticulum retention amino acid sequence, Lys-Asp-Glu-Leu (KDEL), at its carboxyl terminus. The mutant IGF-IA/KDEL precursor expressed by stably transfected FRTL-5 cells was shown to be retained intracellularly and to have biological activity comparable with mature IGF-I, as judged by the activity of partially purified IGF-IA/KDEL in wild type FRTL-5 cells. Expression of IGF-IA/KDEL in FRTL-5 cells, however, neither augmented TSH-stimulated DNA synthesis nor stimulated IGF-binding protein-5 expression, as does IGF-IA expression in transfected FRTL-5 cells and the addition of exogenous IGF-I to wild type FRTL-5 cells. IGF-IA/KDEL expression, however, desensitized FRTL-5 cells to the actions of exogenous IGF-I despite having only minimal effects on cell surface type I receptor number, suggesting that intracellular IGF-I is capable of significant biological actions. The failure of IGF-IA/KDEL to replicate the actions of secreted IGF-I, taken together with the findings that a monoclonal antibody against IGF-I blocked IGF-I's actions in IGF-I-secreting transfected FRTL-5 cells, provides evidence that IGF-I secretion and interaction with cell surface type I IGF receptors is the dominant mechanism of IGF-I's autocrine actions

Insulin-Like Growth Factor-1 Inhibits Mature Oligodendrocyte Apoptosis during Primary Demyelination

Metabolic insult results in apoptosis and depletion of mature oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that continuously express IGF-1

The Cool ISM in Elliptical Galaxies. II. Gas Content in the Volume - Limited Sample and Results from the Combined Elliptical and Lenticular Surveys

We report new observations of atomic and molecular gas in a volume limited sample of elliptical galaxies. Combining the elliptical sample with an earlier and similar lenticular one, we show that cool gas detection rates are very similar among low luminosity E and SO galaxies but are much higher among luminous S0s. Using the combined sample we revisit the correlation between cool gas mass and blue luminosity which emerged from our lenticular survey, finding strong support for previous claims that the molecular gas in ellipticals and lenticulars has different origins. Unexpectedly, however, and contrary to earlier claims, the same is not true for atomic gas. We speculate that both the AGN feedback and merger paradigms might offer explanations for differences in detection rates, and might also point towards an understanding of why the two gas phases could follow different evolutionary paths in Es and S0s. Finally we present a new and puzzling discovery concerning the global mix of atomic and molecular gas in early type galaxies. Atomic gas comprises a greater fraction of the cool ISM in more gas rich galaxies, a trend which can be plausibly explained. The puzzle is that galaxies tend to cluster around molecular-to-atomic gas mass ratios near either 0.05 or 0.5.Comment: 37 pages, including 4 tables and 12 figures. Accepted for publication in the Astrophysical Journa

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

In eukaryotic cells, the inactivation of the cyclic nucleotide signal depends on a complex array of cyclic nucleotide phosphodiesterases (PDEs). Although it has been established that multiple PDE isoenzymes with distinct catalytic properties and regulations coexist in the same cell, the physiological significance of this remarkable complexity is poorly understood. To examine the role of a PDE in cAMP signaling in vivo, we have inactivated the type 4 cAMP-specific PDE (PDE4D) gene, a mammalian homologue of the Drosophila dunce. This isoenzyme is involved in feedback regulation of cAMP levels. Mice deficient in PDE4D exhibit delayed growth as well as reduced viability and female fertility. The decrease in fertility of the null female is caused by impaired ovulation and diminished sensitivity of the granulosa cells to gonadotropins. These pleiotropic phenotypes demonstrate that PDE4D plays a critical role in cAMP signaling and that the activity of this isoenzyme is required for the regulation of growth and fertility

Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth

Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulinreceptorsubstrate-1(IRS-1)mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo

The impact of chorionicity on pregnancy outcome and neurodevelopment at 2 years old among twins born preterm: the EPIPAGE-2 cohort study

OBJECTIVE To compare the short‐ and mid‐term outcomes of preterm twins by chorionicity of pregnancy. DESIGN Prospective nationwide population‐based EPIPAGE‐2 cohort study. SETTING 546 maternity units in France, between March and December 2011. POPULATION A total of 1700 twin neonates born between 24 and 34 weeks of gestation. METHODS The association of chorionicity with outcomes was analysed using multivariate regression models. MAIN OUTCOME MEASURES First, survival at 2‐year corrected age with or without neurosensory impairment, and second, perinatal, short‐, and mid‐term outcomes (survival at discharge, survival at discharge without severe morbidity) were described and compared by chorionicity. RESULTS In the EPIPAGE 2 cohort, 1700 preterm births were included (850 twin pregnancies). In all, 1220 (71.8%) were from dichorionic (DC) pregnancies and 480 from monochorionic (MC) pregnancies. MC pregnancies had three times more medical terminations than DC pregnancies (1.67 versus 0.51%, P < 0.001), whereas there were three times more stillbirths in MC than in DC pregnancies (10.09 versus 3.78%, P < 0.001). Both twins were alive at birth in 86.6% of DC pregnancies compared with 80.0% among MC pregnancies (P = 0.008). No significant difference according to chorionicity was found regarding neonatal deaths and morbidities. Likewise, for children born earlier than 32 weeks, the 2‐year follow‐up neurodevelopmental results were not significantly different between DC and MC twins. CONCLUSIONS This study confirms that MC pregnancies have a higher risk of adverse outcomes. However, the outcomes among preterm twins admitted to neonatal intensive care units are similar irrespective of chorionicity

Radial distribution of the multiple stellar populations in omega Centauri

We present a detailed study of the radial distribution of the multiple populations identified in the Galactic globular cluster omega Cen. We used both space-based images (ACS/WFC and WFPC2) and ground-based images (FORS1@VLT and [email protected] ESO telescopes) to map the cluster from the inner core to the outskirts (~20 arcmin). These data sets have been used to extract high-accuracy photometry for the construction of color-magnitude diagrams and astrometric positions of ~900 000 stars. We find that in the inner ~2 core radii the blue main sequence (bMS) stars slightly dominate the red main sequence (rMS) in number. At greater distances from the cluster center, the relative numbers of bMS stars with respect to rMS drop steeply, out to ~8 arcmin, and then remain constant out to the limit of our observations. We also find that the dispersion of the Gaussian that best fits the color distribution within the bMS is significantly greater than the dispersion of the Gaussian that best fits the color distribution within the rMS. In addition, the relative number of intermediate-metallicity red-giant-branch stars which includes the progeny of the bMS) with respect to the metal-poor component (the progeny of the rMS) follows a trend similar to that of the main-sequence star-count ratio N_bMS/N_rMS. The most metal-rich component of the red-giant branch follows the same distribution as the intermediate-metallicity component. We briefly discuss the possible implications of the observed radial distribution of the different stellar components in omega Cen.Comment: 16 pages, 14 figures (6 in low resolution), 3 tables. Accepted for publication in Astronomy and Astrophysics on 23 September 200