Homeobox Protein Gsh-1-Dependent Regulation of the Rat GHRH Gene Promoter

Mutsuga, Naomi; Iwasaki, Yoshinobu; Morishita, Minako; Nomura, Akihiro; Yamamori, Etsuko; Yoshida, Masanori; Asai, Masato; Ozaki, Nobuaki; Kambe, Fukushi; Seo, Hisao; Oiso, Yutaka; Saito, Hidehiko

doi:10.1210/mend.15.12.0747

Cited by 20 publications

(5 citation statements)

References 23 publications

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“…The intermediate column expressing ind is flanked by a dorsal column expressing muscle segmentation homeobox (msh) and a ventral column expressing ventral neuroblasts defective (vnd) (Weiss et al 1998). One of the two vertebrate gsx paralogs, gsh-1, is likewise expressed in descendants of the intermediate column of the central nervous system (Hsieh-Li et al 1995;Valerius et al 1995;Deschet et al 1998;Mutsuga et al 2001). Furthermore, in a pattern comparable with that of Drosophila, the region expressing gsh-1 is flanked by regions expressing msh/msx and vnd/Nk-2 (Weiss et al 1998).…”

Section: Discussionmentioning

confidence: 98%

Early evolution of a homeobox gene: the parahox gene Gsx in the Cnidaria and the Bilateria

Finnerty

Paulson

Burton

et al. 2003

Evolution and Development

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Homeobox transcription factors are commonly involved in developmental regulation in diverse eukaryotes, including plants, animals, and fungi. The origin of novel homeobox genes is thought to have contributed to many evolutionary innovations in animals. We perform a molecular phylogenetic analysis of cnox2, the best studied homeobox gene from the phylum Cnidaria, a very ancient lineage of animals. Among three competing hypotheses, our analysis decisively favors the hypothesis that cnox2 is orthologous to the gsx gene of Bilateria, thereby establishing the existence of this specific homeobox gene in the eumetazoan stem lineage, some 650-900 million years ago. We assayed the expression of gsx in the planula larva and polyp of the sea anemone Nematostella vectensis using in situ hybridization and reverse transcriptase polymerase chain reaction. The gsx ortholog of Nematostella, known as anthox2, is expressed at high levels in the posterior planula and the corresponding "head" region of the polyp. It cannot be detected in the anterior planula or the corresponding "foot" region of the polyp. We have attempted to reconstruct the evolution of gsx spatiotemporal expression in cnidarians and bilaterians using a phylogenetic framework. Because of the surprisingly high degree of variability in gsx expression within the Cnidaria, it is currently not possible to infer unambiguously the ancestral cnidarian condition or the ancestral eumetazoan condition for gsx expression.

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Section: Discussionmentioning

confidence: 98%

Early evolution of a homeobox gene: the parahox gene Gsx in the Cnidaria and the Bilateria

Finnerty

Paulson

Burton

et al. 2003

Evolution and Development

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“…Homologous recombination techniques have been used to demonstrate that Gsh-1 is the key determinant of GHRH gene expression. Mutsuga et al (4) showed that Gsh-1 is a prerequisite for maintaining the transcriptional activity of the GHRH gene. To investigate whether the mechanism by which BHBA decreased GHRH mRNA expression was Gsh-1dependent, we evaluated the effect of BHBA on Gsh-1 mRNA expression in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…The Gsh-1 homeobox protein plays a key role in the expression of the gene for GHRH. Genetic ablation of Gsh-1 in mice results in the loss of GHRH gene expression in the hypothalamic arcuate nucleus and a dwarf phenotype (3)(4)(5). Although a large number of studies have shown that many factors such as ghrelin, orexin-A and RFRP-3 influence the release of GHRH (6)(7)(8), interactions between extrinsic and intrinsic factors and the molecular mechanisms modulating GHRH secretion still remain to be determined.…”

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confidence: 99%

β‐Hydroxybutyric Acid Inhibits Growth Hormone‐Releasing Hormone Synthesis and Secretion Through the GPR109A/Extracellular Signal‐Regulated 1/2 Signalling Pathway in the Hypothalamus

Liu

Wang

et al. 2015

J Neuroendocrinology

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β-Hydroxybutyric acid (BHBA) has recently been shown to regulate hormone synthesis and secretion in the hypothalamus. However, little is known about the effects of BHBA-mediated hormone regulation or the detailed mechanisms by which BHBA regulates growth hormone-releasing hormone (GHRH) synthesis and secretion. In the present study, we examined the expression of the BHBA receptor GPR109A in primary hypothalamic cell cultures. We hypothesised that BHBA regulates GHRH via GPR109A and its downstream signals. Initial in vivo studies conducted in rats demonstrated that GHRH mRNA expression in the hypothalamus was strongly inversely correlated with BHBA levels in the cerebrospinal fluid during postnatal development (r = -0.89, P < 0.01). Furthermore, i.c.v. administration of BHBA acutely decreased GHRH mRNA expression in rats. Further in vitro studies revealed a decrease in GHRH synthesis and secretion in primary hypothalamic cells after treatment with BHBA; this effect was inhibited when hypothalamic cells were pretreated with pertussis toxin (PTX). BHBA had no effect on GHRH synthesis and secretion in GT1-7 cells, which do not exhibit cell surface expression of GPR109A. Furthermore, BHBA acutely decreased the transcription of the homeobox gene for Gsh-1 in the hypothalamus in both in vivo and in vitro, and this effect was also inhibited by PTX in vitro. In primary hypothalamic cells, BHBA activated the extracellular signal-regulated kinase (ERK)1/2, p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) kinases, as shown by western blot analysis. Moreover, inhibition of ERK1/2 with U0126 attenuated the BHBA-mediated reduction in Gsh-1 expression and GHRH synthesis and secretion. These results strongly suggest that BHBA directly regulates GHRH synthesis and secretion via the GPR109A/ERK1/2 MAPK pathway, and also that Gsh-1 is essential for this function.

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“…The homeobox transcriptional factor Gsh-1 positively regulates the GHRH promoter in cooperation with CREB-binding protein (24). Homozygous inactivation of Gsh-1 leads to a postnatal dwarf phenotype with diminished GHRH expression (25), reminiscent of the Ik-null mouse.…”

Section: Discussionmentioning

confidence: 99%

An essential role for the hematopoietic transcription factor Ikaros in hypothalamic–pituitary-mediated somatic growth

Ezzat

Mader

Fischer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ikaros transcription factors play critical functions in the control of lymphohematopoiesis and immune regulation. Family members contain multiple zinc fingers that mediate DNA binding and homooligomerization or heterooligomerization. Ikaros is abundantly expressed in pituitary mammosomatotrophs, where it deacetylates histone 3 sites on the proximal growth hormone (GH) promoter to silence gene expression. Ikaros-null mice display stunted growth with reduced circulating levels of the GH target factor insulin-like growth factor I (IGF-I). Ikaros-deficient mice have small anterior pituitary glands with a disproportionately reduced somatotroph population. Systemic administration of GH results in increased IGF-I levels and enhanced somatic growth. In contrast, reconstitution with WT lymphocytes was not sufficient to rescue the stunted growth phenotype of Ikaros-deficient mice. Ikaros was identified in mouse hypothalamic arcuate nuclei, where it colocalized with GH-releasing hormone (GHRH); in contrast, Ikaros-null mice lack GHRH immunoreactivity in the hypothalamus. Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression. These findings unmask a wider role for Ikaros in the neuroendocrine system, highlighting a critical contribution to the development of the hypothalamicpituitary somatotrophic axis.growth hormone ͉ growth hormone-releasing hormone ͉ insulin-like growth factor I ͉ somatotrophs

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Homeobox Protein Gsh-1-Dependent Regulation of the Rat GHRH Gene Promoter

Cited by 20 publications

References 23 publications

Early evolution of a homeobox gene: the parahox gene Gsx in the Cnidaria and the Bilateria

Early evolution of a homeobox gene: the parahox gene Gsx in the Cnidaria and the Bilateria

β‐Hydroxybutyric Acid Inhibits Growth Hormone‐Releasing Hormone Synthesis and Secretion Through the GPR109A/Extracellular Signal‐Regulated 1/2 Signalling Pathway in the Hypothalamus

An essential role for the hematopoietic transcription factor Ikaros in hypothalamic–pituitary-mediated somatic growth

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