Growth Hormone Action on Proliferation and Differentiation of Cerebral Cortical Cells from Fetal Rat

Abstract

To define the role of GH during central nervous system development, we performed studies in cultured rat cerebral cortical cells from 14- (E14) and 17-d-old embryos (E17). The expression of GH receptor, IGF-I receptor, and IGF-I mRNAs was confirmed. In E17, GH increased total cell number (3.9-fold), [(3)H]-thymidine incorporation (3.5-fold), proliferating cell nuclear antigen levels (2.5-fold), and bromodeoxyuridine (BrdU)-positive cells (2.5-fold). GH action on nestin/BrdU-positive cells was increased in E14 cells at 3 d in vitro (80-fold) but not at 7 d in vitro. In E14 cells, GH increased (9.5-fold) beta-tubulin/BrdU cells. In E17 cells, GH induced neuronal differentiation, as indicated by the absence of beta-tubulin/BrdU-positive cells and the 5.9-fold increment of beta-tubulin protein, and increased glial fibrillary acidic protein/BrdU-positive cells (2.5-fold) and glial fibrillary acidic protein expression (4.5-fold). GH-induced proliferation and differentiation was blocked by IGF-I antiserum. GH increased IGF-binding protein-3 (IGFBP-3), IGF-I receptor protein and its phosphorylation. This study shows that GH promotes proliferation of neural precursors, neurogenesis, and gliogenesis during brain development. These responses are mediated by locally produced IGF-I. GH-induced IGFBP-3 may also have a role in these responses. Therefore, GH is able to activate the IGF-I/IGFBP-3 system in these cerebral cells and induce a physiological action of IGF-I.

GH in the Central Nervous System: Lessons from the Growth Hormone Receptor Knockout Mouse

“…Additionally, GH has been shown to enhance proliferation of certain cells of the CNS. For example, incubation of fetal rat cerebral cortical cells with recombinant hGH results in increased proliferation in a time and dose-dependent manner [8]. GH is also reported to increase the proliferation of cortical cell precursors and astrocytes [8].…”

“…Despite several lines of evidence from both in vivo and in vitro studies suggesting a role for GH in the CNS [5][6][7][8], the data are often contradictory. For example, studies of animals with elevated GH have shown improvements in memory and learning [9,10], but similar results have been reported using animal models of reduced GH action [11][12][13].…”

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia

“…Increases in IL-1b concentrations, and possibly other cytokines, in the fetal circulation could influence fetal brain development directly, or indirectly, via the modulation of secondary mediators such as insulinlike growth hormone-1 (IGF-1), which was shown to be significantly reduced in the brains of animals injected systemically with IL-1b. 55 As IGF-1 induces neuronal proliferation and differentiation in the fetal rat brain, 56 it is possible that IL-1b-dependent decreases in IGF-1 might disrupt the normal growth and development of the fetal brain, leading to long-term behavioral alterations of relevance to schizophrenia.…”

Differential effects of GH and GH-releasing peptide-6 on astrocytes

“…In fact, activation of the Gfap gene promoter has been related to decreased astrocyte proliferation (Gomes et al 1999b). Although GH promotes the proliferation of neural precursors, neurogenesis and gliogenesis during brain development (Ajo et al 2003), in our adult rats, GH did not induce proliferation but may induce astrocyte differentiation or activation. To further characterise the cellular differentiation stimulated by GH, we studied the levels of another protein of the cytoskeleton, vimentin.…”

“…Indeed, the GH receptor (GHR) is expressed in diverse areas throughout the CNS (Fraser et al 1990, Le Greves et al 2005 where this hormone has been shown to be involved in numerous cellular activities such as stimulation of mitosis, cell proliferation and differentiation (Frago et al 2002, Ajo et al 2003. Binding of GH to its receptor mediates many of its effects through activation of the JAK/STAT signalling pathway (Lanning & Carter-Su 2006); however, GHR is also able to signal through additional pathways including the MAPK and the phosphatidylinositol 3 0 -kinase (PI3K; Brooks et al 2008) pathways.…”