Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta

Sandell, Lisa L.; Guan, Xiao-Juan; Ingram, Robert S.; Tilghman, Shirley M.

doi:10.1073/pnas.0230424100

Cited by 72 publications

(47 citation statements)

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“…It was expressed in the placenta and the yolk sac of mouse embryos. However, no expression was found in the embryonic tissues of mouse (Sandell et al, 2003). Similarly, human agat was also expressed in the placentas (Monk et al, 2006).…”

mentioning

confidence: 90%

Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

Wang¹,

Zhang²,

Shao³

et al. 2007

Int. J. Dev. Biol.

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Glycine amidinotransferase (AGAT or GATM), guanidinoacetate methyltransferase (GAMT) and creatine transporter (CT1) are three proteins involved in the synthesis and uptake of creatine. The expression patterns of these three genes were examined in zebrafish embryos by whole mount in situ hybridization followed by histological sectioning. Expression of agat first appeared in the yolk syncytial layer (YSL) at the gastrula stage and was progressively up regulated during gastrulation. As development proceeds, agat was expressed in the mature somites during the segmentation stage and in the liver at 48 hpf. gamt showed a similar expression pattern to that of agat during embryogenesis. It was first detected in the center of the yolk from the cleavage to the gastrula stage. At the bud stage, its expression shifted to the YSL. gamt was also transiently expressed in the mature somites from 16 hpf to 24 hpf and became strongly expressed in the liver and in epithelial cells of the gut at 48 hpf. ct1 was initially uniformly expressed from the cleavage to the early segmentation stage; it was then strongly expressed in all the somites till 30 hpf and in the gut of 48 hpf embryos. However, ct1 transcripts also appeared in the central nervous system during the segmentation stage, but not in the YSL, the yolk or the liver. Our data reveal for the first time distinct and unique patterns of expression of the creatine metabolism genes agat, gamt and ct1 during zebrafish embryogenesis. KEY WORDS: agat, gamt, ct1, zebrafish, developmental expressionThe creatine metabolism plays a crucial role for keeping the normal life of vertebrates. Endogenous creatine is synthesized by a two-step mechanism involving two enzymes: glycine amidinotransferase (AGAT or GATM) and guanidinoacetate methyltransferase (GAMT). Creatine is taken up by cells through CT1, a specific creatine transporter (Wyss and KaddurahDaouk, 2000). Defects of AGAT, GAMT and CT1 result in three kinds of creatine deficiency syndromes (CDS) occurring mostly in children (Schulze, 2003). The common clinical feature of three CDS is developmental delay/regression, mental retardation and severe disturbance of their expressive and cognitive speech (van der . The biochemical characteristics of CDS include severe depletion of creatine/phosphocreatine in the brain, as well as changes in creatine and creatinine concentrations in body fluids , Cecil et al., 2001, Schulze, 2003, Stromberger et al., 2003, Almeida et al., 2004, Sykut-Cegielska et al., 2004. GAMT deficiency is characterized by accumulation of guanidinoacetic acid in brain and body fluids and shows intrac- Abbreviations used in this paper: AGAT (or GATM), glycine amidinotransferase; GAMT, guanidinoacetate methyltransferase; CDS, creatine deficiency syndromes; CT1, creatine transporter 1; YSL, yolk syncytial layer. al., 2004). GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CT1 defect is an X-linked disorder (Mancini et al., 2005. Treatment with oral creatine supplementation is in part successful ...

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mentioning

confidence: 90%

Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

Wang¹,

Zhang²,

Shao³

et al. 2007

Int. J. Dev. Biol.

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“…On the other hand, AGAT, GAMT and SLC6A8 are also well expressed during vertebrate embryogenesis, including in the brain (Schloss et al 1994;Sandell et al 2003;Schmidt et al 2004;Braissant et al 2005;Wang et al 2007;Ireland et al 2009). We have shown that AGAT and GAMT are expressed in the whole developing CNS parenchyma (Braissant et al 2005).…”

Section: Adult Versus Developmental Cnsmentioning

confidence: 99%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

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“…We have analyzed the human imprinted expression of genes on other chromosomes that exhibit placental-specific imprinting in the mouse, glycine amidinotransferase (Gatm) (mChr2) and decorin (Dcn) (mChr10) (26,27). In the mouse, both are isolated imprinted genes without associated DMRs.…”

Section: Allelic Expression and Methylation Within The Kcnq1 Domainmentioning

confidence: 99%

Limited evolutionary conservation of imprinting in the human placenta

Monk

Arnaud

Apostolidou

et al. 2006

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

234

205

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The epigenetic phenomenon of genomic imprinting provides an additional level of gene regulation that is confined to a limited number of genes, frequently, but not exclusively, important for embryonic development. The evolution and maintenance of imprinting has been linked to the balance between the allocation of maternal resources to the developing fetus and the mother's well being. Genes that are imprinted in both the embryo and extraembryonic tissues show extensive conservation between a mouse and a human. Here we examine the human orthologues of mouse genes imprinted only in the placenta, assaying allele-specific expression and epigenetic modifications. The genes from the KCNQ1 domain and the isolated human orthologues of the imprinted genes Gatm and Dcn all are expressed biallelically in the human, from first-trimester trophoblast through to term. This lack of imprinting is independent of promoter CpG methylation and correlates with the absence of the allelic histone modifications dimethylation of lysine-9 residue of H3 (H3K9me2) and trimethylation of lysine-27 residue of H3 (H3K27me3). These specific histone modifications are thought to contribute toward regulation of imprinting in the mouse. Genes from the IGF2R domain show polymorphic concordant expression in the placenta, with imprinting demonstrated in only a minority of samples. Together these findings have important implications for understanding the evolution of mammalian genomic imprinting. Because most human pregnancies are singletons, this absence of competition might explain the comparatively relaxed need in the human for placentalspecific imprinting.histones ͉ methylation ͉ epigenetics

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Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta

Cited by 72 publications

References 50 publications

Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Limited evolutionary conservation of imprinting in the human placenta

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