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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

Expression profile of mouse Sirh11/Zcchc16 mRNA.(A) Exon-intron structure of the Sirh11/Zcchc16 gene. The full-length cDNA sequence was identified by 5'- and 3'-RACE (Rapid Amplification of cDNA Ends) experiments using brain RNA at 8 w. The Sirh11/Zcchc16 gene consists of 7 exons and the protein coding sequence is in exon 7. The identified cDNA sequence corresponds to Genbank Accession No. NM_001033795.4. The white and black boxes represent the exons and ORF, respectively. (B) Sirh11 expression in fetuses and adults. qRT-PCR analyses were carried out using C57BL/6J cDNA from various tissues and organs at d14.5 and 8 w. The black and white bars indicate males and females, respectively. Data represents the mean ± S. D. (N = 3 each). Sirh11/Zcchc16 expression was observed in the brain, testis, ovary and kidney, but not in the placenta. qRT-PCR primers (F9R9) were designed in the 3’ UTR region of Sirh11/Zcchc16 mRNA (see arrows in Fig 2A). (C) Overexpression of the Sirh11/Zcchc16 transcript without any ORF in KO mice. The graph shows the Sirh11/Zcchc16 expression levels at 8 weeks of age using F9R9 (3’ UTR) primer sets relative to Actb mRNA in the male brain, kidney and testis. The white and black bars represent WT and KO, respectively. Each data point represents the mean ± S. D. (N = 4 each). The asterisks indicate significant differences between the WT and KO mice (**: p < 0.01).
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pgen.1005521.g002: Expression profile of mouse Sirh11/Zcchc16 mRNA.(A) Exon-intron structure of the Sirh11/Zcchc16 gene. The full-length cDNA sequence was identified by 5'- and 3'-RACE (Rapid Amplification of cDNA Ends) experiments using brain RNA at 8 w. The Sirh11/Zcchc16 gene consists of 7 exons and the protein coding sequence is in exon 7. The identified cDNA sequence corresponds to Genbank Accession No. NM_001033795.4. The white and black boxes represent the exons and ORF, respectively. (B) Sirh11 expression in fetuses and adults. qRT-PCR analyses were carried out using C57BL/6J cDNA from various tissues and organs at d14.5 and 8 w. The black and white bars indicate males and females, respectively. Data represents the mean ± S. D. (N = 3 each). Sirh11/Zcchc16 expression was observed in the brain, testis, ovary and kidney, but not in the placenta. qRT-PCR primers (F9R9) were designed in the 3’ UTR region of Sirh11/Zcchc16 mRNA (see arrows in Fig 2A). (C) Overexpression of the Sirh11/Zcchc16 transcript without any ORF in KO mice. The graph shows the Sirh11/Zcchc16 expression levels at 8 weeks of age using F9R9 (3’ UTR) primer sets relative to Actb mRNA in the male brain, kidney and testis. The white and black bars represent WT and KO, respectively. Each data point represents the mean ± S. D. (N = 4 each). The asterisks indicate significant differences between the WT and KO mice (**: p < 0.01).

Mentions: Sirh11/Zcchc16 is basically comprised of 7 exons, with its ORF in the last exon (Fig 2A). According to the NCBI database, there are at least three variants with different first exon sequences, presumably dependent on the tissues and organs where it resides. A low level of Sirh11/Zcchc16 expression was observed in the brain, liver and heart on embryonic day 14.5 (d14.5), with a moderate level of expression in the brain, kidney, testis and ovary in adults (8 weeks (8 w)) (Fig 2B). We generated Sirh11/Zcchc16 KO mice using TT2 ES cells by means of a complete deletion of its protein coding sequence (S2 Fig). After removing the neomycin cassette, Sirh11/Zcchc16 KO mice were backcrossed to B6 more than 10 generations. We confirmed the lack of the ORF region by RT-PCR using a primer set (F5R5). However, it should be noted that the RT-PCR experiment using primer sets amplifying its 3’-UTR region (such as F9R9) exhibited an approximately 1.5 fold increment in these organs in the KO mice (although not significant in the whole brain or kidney), suggesting the existence of a feedback mechanism regulating Sirh11/Zcchc16 at the protein level (Fig 2A and 2C).


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)

Expression profile of mouse Sirh11/Zcchc16 mRNA.(A) Exon-intron structure of the Sirh11/Zcchc16 gene. The full-length cDNA sequence was identified by 5'- and 3'-RACE (Rapid Amplification of cDNA Ends) experiments using brain RNA at 8 w. The Sirh11/Zcchc16 gene consists of 7 exons and the protein coding sequence is in exon 7. The identified cDNA sequence corresponds to Genbank Accession No. NM_001033795.4. The white and black boxes represent the exons and ORF, respectively. (B) Sirh11 expression in fetuses and adults. qRT-PCR analyses were carried out using C57BL/6J cDNA from various tissues and organs at d14.5 and 8 w. The black and white bars indicate males and females, respectively. Data represents the mean ± S. D. (N = 3 each). Sirh11/Zcchc16 expression was observed in the brain, testis, ovary and kidney, but not in the placenta. qRT-PCR primers (F9R9) were designed in the 3’ UTR region of Sirh11/Zcchc16 mRNA (see arrows in Fig 2A). (C) Overexpression of the Sirh11/Zcchc16 transcript without any ORF in KO mice. The graph shows the Sirh11/Zcchc16 expression levels at 8 weeks of age using F9R9 (3’ UTR) primer sets relative to Actb mRNA in the male brain, kidney and testis. The white and black bars represent WT and KO, respectively. Each data point represents the mean ± S. D. (N = 4 each). The asterisks indicate significant differences between the WT and KO mice (**: p < 0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581854&req=5

pgen.1005521.g002: Expression profile of mouse Sirh11/Zcchc16 mRNA.(A) Exon-intron structure of the Sirh11/Zcchc16 gene. The full-length cDNA sequence was identified by 5'- and 3'-RACE (Rapid Amplification of cDNA Ends) experiments using brain RNA at 8 w. The Sirh11/Zcchc16 gene consists of 7 exons and the protein coding sequence is in exon 7. The identified cDNA sequence corresponds to Genbank Accession No. NM_001033795.4. The white and black boxes represent the exons and ORF, respectively. (B) Sirh11 expression in fetuses and adults. qRT-PCR analyses were carried out using C57BL/6J cDNA from various tissues and organs at d14.5 and 8 w. The black and white bars indicate males and females, respectively. Data represents the mean ± S. D. (N = 3 each). Sirh11/Zcchc16 expression was observed in the brain, testis, ovary and kidney, but not in the placenta. qRT-PCR primers (F9R9) were designed in the 3’ UTR region of Sirh11/Zcchc16 mRNA (see arrows in Fig 2A). (C) Overexpression of the Sirh11/Zcchc16 transcript without any ORF in KO mice. The graph shows the Sirh11/Zcchc16 expression levels at 8 weeks of age using F9R9 (3’ UTR) primer sets relative to Actb mRNA in the male brain, kidney and testis. The white and black bars represent WT and KO, respectively. Each data point represents the mean ± S. D. (N = 4 each). The asterisks indicate significant differences between the WT and KO mice (**: p < 0.01).
Mentions: Sirh11/Zcchc16 is basically comprised of 7 exons, with its ORF in the last exon (Fig 2A). According to the NCBI database, there are at least three variants with different first exon sequences, presumably dependent on the tissues and organs where it resides. A low level of Sirh11/Zcchc16 expression was observed in the brain, liver and heart on embryonic day 14.5 (d14.5), with a moderate level of expression in the brain, kidney, testis and ovary in adults (8 weeks (8 w)) (Fig 2B). We generated Sirh11/Zcchc16 KO mice using TT2 ES cells by means of a complete deletion of its protein coding sequence (S2 Fig). After removing the neomycin cassette, Sirh11/Zcchc16 KO mice were backcrossed to B6 more than 10 generations. We confirmed the lack of the ORF region by RT-PCR using a primer set (F5R5). However, it should be noted that the RT-PCR experiment using primer sets amplifying its 3’-UTR region (such as F9R9) exhibited an approximately 1.5 fold increment in these organs in the KO mice (although not significant in the whole brain or kidney), suggesting the existence of a feedback mechanism regulating Sirh11/Zcchc16 at the protein level (Fig 2A and 2C).

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