Role of the 5′ enhancer of the glutamine synthetase gene in its organ-specific expression

Lie-Venema, Heleen; Boer, Piet A. J. de; Moorman, Antoon F.M.; Lamers, Wouter H.

doi:10.1042/bj3230611

Cited by 29 publications

(18 citation statements)

References 60 publications

(69 reference statements)

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“…This distribution of LacZ‐positive cells is consistent with the normal distribution of GS‐positive cells in non‐chimeric littermate embryos (e.g., Fig. 6H); see also previous studies (Lie‐Venema et al, 1997a, b). Immunohistochemistry on serial sections of chimeric embryos showed that the GS‐positive wild‐type cells (GS +/+ ) had a complementary distribution pattern to LacZ‐positive cells (GS GFP/LacZ ) (e.g., Fig.…”

Section: Resultssupporting

confidence: 91%

Glutamine synthetase is essential in early mouse embryogenesis

Hakvoort

Vermeulen

et al. 2007

Developmental Dynamics

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Glutamine synthetase (GS) is expressed in a tissue-specific and developmentally controlled manner, and functions to remove ammonia or glutamate. Furthermore, it is the only enzyme that can synthesize glutamine de novo. Since congenital deficiency of GS has not been reported, we investigated its role in early development. Because GS is expressed in embryonic stem (ES) cells, we generated a null mutant by replacing one GS allele in-frame with a ␤-galactosidase-neomycine fusion gene. GS ؉/LacZ mice have no phenotype, but GS LacZ/LacZ mice die at ED3.5, demonstrating GS is essential in early embryogenesis. Although cells from ED2.5 GS LacZ/LacZ embryos and GS GFP/LacZ ES cells survive in vitro in glutaminecontaining medium, these GS-deficient cells show a reduced fitness in chimera analysis and fail to survive in tetraploid-complementation assays. The survival of heavily (>90%) chimeric mice up to at least ED16.5 indicates that GS deficiency does not entail cell-autonomous effects and that, after implantation, GS activity is not essential until at least the fetal period. We hypothesize that GS-deficient embryos die when they move from the uterine tube to the harsher uterine environment, where the embryo has to catabolize amino acids to generate energy and, hence, has to detoxify ammonia, which requires GS activity. Developmental Dynamics 236:1865-1875, 2007.

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Section: Resultssupporting

confidence: 91%

Glutamine synthetase is essential in early mouse embryogenesis

Hakvoort

Vermeulen

et al. 2007

Developmental Dynamics

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“…6). This hypothesis is based on: (1) the lack ornithine decarboxylase (ODC; EC 4.1.1.17), the key enzyme of the polyamine pathway [27], (2) the high level of expression of the mitochondrial ornithine aminotransferase (OAT; EC 2.6.1.13) in the three subsegments of the proximal tubule [27], and (3) the expression of glutamine synthetase (GS; EC 6.3.1.2) that converts L-glutamate into L-glutamine in the presence of ATP and one ammonium ion, in the entire proximal tubule [18,29]. Because AII, OAT and GS genes are expressed in the pars recta of the proximal tubule (CPST and OSPST), L-arginine may be metabolized into L-ornithine, glutamate-c-semialdehyde and L-glutamate in the mitochondria, whereas the production of L-glutamine occurs in the cytosol (Fig.…”

Section: Discussionmentioning

confidence: 99%

Localization and differential expression of arginase II in the kidney of male and female mice

Levillain

Balvay

Peyrol

2004

Pflugers Arch - Eur J Physiol

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Arginase II (AII) has been almost exclusively studied in male mammalian kidneys. Our investigations were conducted to localize AII gene expression in the female mouse kidney, and to analyze the differential expression of AII gene at the transcriptional and translational levels in the kidneys of female and male mice. Total RNAs and soluble proteins extracted from renal zones and whole kidneys were analyzed by Northern and Western blots, respectively. Mitochondrial and cytosolic proteins were analyzed by Western blot. L-[guanidino-14C]arginine hydrolysis by AII was detected in microdissected tubules and the 14CO2 released from [14C]urea hydrolysis was quantified. The results of these experiments showed that: (1) both AII mRNA and protein were highly expressed in the deep cortex and the outer stripe of the outer medulla, (2) urea was produced mainly in the proximal straight tubules (PST), (3) the 38-kDa AII protein was more abundant in the mitochondria than the cytosol, and (4) the renal content of AII mRNA and protein was about three-fold higher in female than in male mice. In conclusion, in both genders, AII gene expression is restricted to the PST and localized into mitochondria. AII gene is differentially expressed in the kidney of female and male mice since higher levels of AII mRNA, protein and activity were observed in the kidneys of the former than those of the latter. Renal AII gene expression was gender-dependent in mice but not in rats. Finally, in the PST of females, L-arginine-derived ornithine may be a precursor for the renal production of L -glutamate and L-glutamine because high levels of AII, ornithine aminotransferase and glutamine synthetase are expressed in this nephron segment.

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“…Although the 5Јupstream enhancer of the GS gene was identified several years ago (21) and described to be responsible for GS expression in several organs (23) there was no further information available aside from a crude localisation of the element. At the time we started the work presented the element was located within a 370 bp long 5Јupstream region marked by a HindIII site at Ϫ2516 and an EcoRV site at Ϫ2146.…”

Section: Discussionmentioning

confidence: 98%

“…In transient transfection experiments with cells from the human hepatoblastoma cell line HepG2 we were already able to demonstrate that defined sequences from the first intron (19) and from the 5Ј-upstream region including the homologous promoter (20) contribute to the expression of the enzyme. In the work presented here we aimed at the distal enhancer of the GS gene roughly determined to be located between a HindIII site at Ϫ2516 and an EcoRV site at Ϫ2146 that appeared to be of importance for the high level of expression in hepatocytes (21) and also in other organs (22,23). Since nothing was known about the exact position of the cis-element nor anything about factors binding to it we decided to investigate the 5Ј-upstream region by gel mobility shift experiments and reportergene assays with different fragments of DNA from this region.…”

mentioning

confidence: 99%