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Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.

Irie M, Yoshikawa M, Ono R, Iwafune H, Furuse T, Yamada I, Wakana S, Yamashita Y, Abe T, Ishino F, Kaneko-Ishino T - PLoS Genet. (2015)

Bottom Line: Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein.Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice.Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1.

View Article: PubMed Central - PubMed

Affiliation: School of Health Sciences, Tokai University, Isehara, Kanagawa, Japan; Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Gene targeting of mouse Sushi-ichi-related retrotransposon homologue 11/Zinc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1.

No MeSH data available.


Related in: MedlinePlus

Abnormality in brain of Sirh11/Zcchc16 KO mice.(A) Microdialysis analysis in the prefrontal cortex in the cerebrum. The levels of various monoamines, including DA, NA, 3-MT and DOPAC were measured after perfusion of high potassium-containing artificial cerebrospinal fluid in the prefrontal cortex. Each plot shows the ratio of the DA metabolites, NA, 3-MT and DOPAC, to DA. The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). The three lines on the plots indicate the mean ± S. E. M. (B) Dbh mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Dbh to Actb mRNA in WT and KO, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO (*: p < 0.05). The expression levels in the mesencephalon and brainstem are shown in a separate figure with a different scale. (C) Sirh11 mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Sirh11 (3’ UTR) to Actb mRNA in the WT and KO mice, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). (D) Negative correlation between Sirh11/Zcchc16 and Dbh mRNA expression levels in the brainstem. The plots show the relative expression levels of Sirh11 (x-axis) and Dbh (y-axis) to Actb mRNA in the brainstem. The white, black and grey circles indicate the WT, KO and B6, respectively. The Pearson correlation coefficient (r) is shown in the plots. The p-value was calculated by the test for non-correlation.
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pgen.1005521.g004: Abnormality in brain of Sirh11/Zcchc16 KO mice.(A) Microdialysis analysis in the prefrontal cortex in the cerebrum. The levels of various monoamines, including DA, NA, 3-MT and DOPAC were measured after perfusion of high potassium-containing artificial cerebrospinal fluid in the prefrontal cortex. Each plot shows the ratio of the DA metabolites, NA, 3-MT and DOPAC, to DA. The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). The three lines on the plots indicate the mean ± S. E. M. (B) Dbh mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Dbh to Actb mRNA in WT and KO, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO (*: p < 0.05). The expression levels in the mesencephalon and brainstem are shown in a separate figure with a different scale. (C) Sirh11 mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Sirh11 (3’ UTR) to Actb mRNA in the WT and KO mice, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). (D) Negative correlation between Sirh11/Zcchc16 and Dbh mRNA expression levels in the brainstem. The plots show the relative expression levels of Sirh11 (x-axis) and Dbh (y-axis) to Actb mRNA in the brainstem. The white, black and grey circles indicate the WT, KO and B6, respectively. The Pearson correlation coefficient (r) is shown in the plots. The p-value was calculated by the test for non-correlation.

Mentions: We carried out microdialysis analysis in the prefrontal cortex of the cerebrum to directly examine the monoamine levels in the KO brain [34–35] because it is well documented that prefrontal cortical NA as well as dopamine (DA) plays an important role in spatial working memory [36]. The levels of various monoamines were measured, mainly at 11~13 w of age, including DA, NA, adrenaline (AD), 3-methoxytyramine (3-MT), 5-hydroxyindole acetic acid (5-HIAA), serotonin (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methyl-4-hydroxy-phenylglycol (MHPG) and normetanephrine (NM) using isoproterenol (ISO) as the control. During overnight experiments for long-term recording, we found that these levels varied suddenly and unexpectedly, presumably because of abrupt changes in sound and vibration in the experiment room. The levels were also greatly dependent on the initial condition of the mice. As it was difficult to obtain reproducible data in the normal experimental setting, we adopted the perfusion method to overcome this difficulty. Perfusion by high-K solution intensively stimulates the release of neurotransmitters and hence enables an evaluation of the sum of neurotransmitter content at the synapse and in the neuron. High K solution was applied twice, with a 120-min interval. The release of neurotransmitter in response to the second perfusion of the high K solution is dependent upon the catabolic activity during a 120 min period. It was demonstrated that the recovery of the NA level was significantly delayed compared with the DA level (Mann-Whitney U test, p = 0.0159), while the levels of two other DA metabolites, DOPAC and 3-MT (Mann-Whitney U test, p = 0.532 and 0.310, respectively), were unchanged in the KO mice (Fig 4A).


Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.

Irie M, Yoshikawa M, Ono R, Iwafune H, Furuse T, Yamada I, Wakana S, Yamashita Y, Abe T, Ishino F, Kaneko-Ishino T - PLoS Genet. (2015)

Abnormality in brain of Sirh11/Zcchc16 KO mice.(A) Microdialysis analysis in the prefrontal cortex in the cerebrum. The levels of various monoamines, including DA, NA, 3-MT and DOPAC were measured after perfusion of high potassium-containing artificial cerebrospinal fluid in the prefrontal cortex. Each plot shows the ratio of the DA metabolites, NA, 3-MT and DOPAC, to DA. The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). The three lines on the plots indicate the mean ± S. E. M. (B) Dbh mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Dbh to Actb mRNA in WT and KO, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO (*: p < 0.05). The expression levels in the mesencephalon and brainstem are shown in a separate figure with a different scale. (C) Sirh11 mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Sirh11 (3’ UTR) to Actb mRNA in the WT and KO mice, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). (D) Negative correlation between Sirh11/Zcchc16 and Dbh mRNA expression levels in the brainstem. The plots show the relative expression levels of Sirh11 (x-axis) and Dbh (y-axis) to Actb mRNA in the brainstem. The white, black and grey circles indicate the WT, KO and B6, respectively. The Pearson correlation coefficient (r) is shown in the plots. The p-value was calculated by the test for non-correlation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581854&req=5

pgen.1005521.g004: Abnormality in brain of Sirh11/Zcchc16 KO mice.(A) Microdialysis analysis in the prefrontal cortex in the cerebrum. The levels of various monoamines, including DA, NA, 3-MT and DOPAC were measured after perfusion of high potassium-containing artificial cerebrospinal fluid in the prefrontal cortex. Each plot shows the ratio of the DA metabolites, NA, 3-MT and DOPAC, to DA. The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). The three lines on the plots indicate the mean ± S. E. M. (B) Dbh mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Dbh to Actb mRNA in WT and KO, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO (*: p < 0.05). The expression levels in the mesencephalon and brainstem are shown in a separate figure with a different scale. (C) Sirh11 mRNA expression in each part of the brain. The white and black bars represent the relative expression levels of Sirh11 (3’ UTR) to Actb mRNA in the WT and KO mice, respectively (mean ± S. D., N = 4 each). The asterisk indicates a significant difference between the WT and KO mice (*: p < 0.05). (D) Negative correlation between Sirh11/Zcchc16 and Dbh mRNA expression levels in the brainstem. The plots show the relative expression levels of Sirh11 (x-axis) and Dbh (y-axis) to Actb mRNA in the brainstem. The white, black and grey circles indicate the WT, KO and B6, respectively. The Pearson correlation coefficient (r) is shown in the plots. The p-value was calculated by the test for non-correlation.
Mentions: We carried out microdialysis analysis in the prefrontal cortex of the cerebrum to directly examine the monoamine levels in the KO brain [34–35] because it is well documented that prefrontal cortical NA as well as dopamine (DA) plays an important role in spatial working memory [36]. The levels of various monoamines were measured, mainly at 11~13 w of age, including DA, NA, adrenaline (AD), 3-methoxytyramine (3-MT), 5-hydroxyindole acetic acid (5-HIAA), serotonin (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methyl-4-hydroxy-phenylglycol (MHPG) and normetanephrine (NM) using isoproterenol (ISO) as the control. During overnight experiments for long-term recording, we found that these levels varied suddenly and unexpectedly, presumably because of abrupt changes in sound and vibration in the experiment room. The levels were also greatly dependent on the initial condition of the mice. As it was difficult to obtain reproducible data in the normal experimental setting, we adopted the perfusion method to overcome this difficulty. Perfusion by high-K solution intensively stimulates the release of neurotransmitters and hence enables an evaluation of the sum of neurotransmitter content at the synapse and in the neuron. High K solution was applied twice, with a 120-min interval. The release of neurotransmitter in response to the second perfusion of the high K solution is dependent upon the catabolic activity during a 120 min period. It was demonstrated that the recovery of the NA level was significantly delayed compared with the DA level (Mann-Whitney U test, p = 0.0159), while the levels of two other DA metabolites, DOPAC and 3-MT (Mann-Whitney U test, p = 0.532 and 0.310, respectively), were unchanged in the KO mice (Fig 4A).

Bottom Line: Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein.Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice.Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1.

View Article: PubMed Central - PubMed

Affiliation: School of Health Sciences, Tokai University, Isehara, Kanagawa, Japan; Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Gene targeting of mouse Sushi-ichi-related retrotransposon homologue 11/Zinc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1.

No MeSH data available.


Related in: MedlinePlus