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The Rat Homolog of the Schizophrenia Susceptibility Gene ZNF804A Is Highly Expressed during Brain Development, Particularly in Growth Cones.

Hinna KH, Rich K, Fex-Svenningsen Å, Benedikz E - PLoS ONE (2015)

Bottom Line: We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels.Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones.In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

ABSTRACT
A single nucleotide polymorphism in the ZNF804A gene, rs1344706, is associated with schizophrenia. The polymorphism has been suggested to alter fetal expression of ZNF804A. It has also been reported to be associated with altered cortical functioning and neural connectivity in the brain. Since developmental mechanisms are suggested in the pathophysiology for schizophrenia, expression of Zfp804A, the rat homolog of ZNF804A, was investigated in the developing rat brain. We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels. This time point is developmentally the equivalent to the second trimester of fetal development in humans. An exception to this expression pattern is the hippocampus where the expression of Zfp804A appears to increase again in the adult brain. Using laser capture and quantitative PCR we found that Zfp804A mRNA expression in the adult rat hippocampus is highest in the CA1 sub region, where the overall firing rates of neurons is higher than in the CA3 region. In cultured cortical neurons Zfp804A mRNA expression peaked at day 4 and then decreased. The ZFP804A protein expression was therefore investigated with immunochemistry in such cultures. Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones. In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation. We also show that ZFP804A is localized to growth cones of growing neurites. These data implicate ZFP804A in growth cone function and neurite elongation. The polymorphism rs1344706 lowers expression of ZNF804A during prenatal brain development. This may affect ZNF804A's role in cone function and neurite elongation leading to synaptic deficits and altered neural connectivity.

No MeSH data available.


Related in: MedlinePlus

Zfp804A mRNA expression in the developing rat brain.(A) Relative Zfp804A mRNA expression in the frontal part of the rat cortex. Zfp804A expression is significantly increased at E18, P1 and P3 compared to the levels at E16 (***P<0.001) and after P3 the level decreases significantly compared to P1 (§§P<0.01, §§§P<0.001). (B) Relative Zfp804A expression in the rat cerebellum. The expression of Zfp804A is significantly higher at E18 and P1 compared to E16 (***P<0.001) and lower at all time points compared to P1 (§§§P<0.001) except for E18. (C) Relative Zfp804A expression within the rat hippocampus. Expression is significantly increased in the adult rat compared to P5 (*P<0.05). The zfp804A primer set was used and data are presented as means ± SEM. Gapdh was used as a reference gene and n ≥ 4
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pone.0132456.g001: Zfp804A mRNA expression in the developing rat brain.(A) Relative Zfp804A mRNA expression in the frontal part of the rat cortex. Zfp804A expression is significantly increased at E18, P1 and P3 compared to the levels at E16 (***P<0.001) and after P3 the level decreases significantly compared to P1 (§§P<0.01, §§§P<0.001). (B) Relative Zfp804A expression in the rat cerebellum. The expression of Zfp804A is significantly higher at E18 and P1 compared to E16 (***P<0.001) and lower at all time points compared to P1 (§§§P<0.001) except for E18. (C) Relative Zfp804A expression within the rat hippocampus. Expression is significantly increased in the adult rat compared to P5 (*P<0.05). The zfp804A primer set was used and data are presented as means ± SEM. Gapdh was used as a reference gene and n ≥ 4

Mentions: The mRNA levels of Zfp804A were investigated in different rat brain regions from animals aged E16 to adult to determine if the expression of this protein is stable or changes over time. At E16, the levels of Zfp804A mRNA were low in the frontal cortex and cerebellum. Shortly before birth, at E18, the levels increase 3–5 fold, peaking at postnatal day 1 (P1). The mRNA levels dropped again at postnatal day 5 (P5) in the frontal cortex and P3 in cerebellum (Fig 1A and 1B) to levels similar to those found in adult brain. The levels of Zfp804A mRNA are thus significantly increased in E18, P1 and P3 frontal cortex compared to the levels at E16 (P<0.001). In the cerebellum the levels were significantly higher at E18 and P1 compared to E16 (P<0.001). In both the frontal cortex and cerebellum, the levels of Zfp804A mRNA were significantly lower a few days after birth, compared to the peak values at E18 and P1 (P<0.01).


The Rat Homolog of the Schizophrenia Susceptibility Gene ZNF804A Is Highly Expressed during Brain Development, Particularly in Growth Cones.

Hinna KH, Rich K, Fex-Svenningsen Å, Benedikz E - PLoS ONE (2015)

Zfp804A mRNA expression in the developing rat brain.(A) Relative Zfp804A mRNA expression in the frontal part of the rat cortex. Zfp804A expression is significantly increased at E18, P1 and P3 compared to the levels at E16 (***P<0.001) and after P3 the level decreases significantly compared to P1 (§§P<0.01, §§§P<0.001). (B) Relative Zfp804A expression in the rat cerebellum. The expression of Zfp804A is significantly higher at E18 and P1 compared to E16 (***P<0.001) and lower at all time points compared to P1 (§§§P<0.001) except for E18. (C) Relative Zfp804A expression within the rat hippocampus. Expression is significantly increased in the adult rat compared to P5 (*P<0.05). The zfp804A primer set was used and data are presented as means ± SEM. Gapdh was used as a reference gene and n ≥ 4
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493006&req=5

pone.0132456.g001: Zfp804A mRNA expression in the developing rat brain.(A) Relative Zfp804A mRNA expression in the frontal part of the rat cortex. Zfp804A expression is significantly increased at E18, P1 and P3 compared to the levels at E16 (***P<0.001) and after P3 the level decreases significantly compared to P1 (§§P<0.01, §§§P<0.001). (B) Relative Zfp804A expression in the rat cerebellum. The expression of Zfp804A is significantly higher at E18 and P1 compared to E16 (***P<0.001) and lower at all time points compared to P1 (§§§P<0.001) except for E18. (C) Relative Zfp804A expression within the rat hippocampus. Expression is significantly increased in the adult rat compared to P5 (*P<0.05). The zfp804A primer set was used and data are presented as means ± SEM. Gapdh was used as a reference gene and n ≥ 4
Mentions: The mRNA levels of Zfp804A were investigated in different rat brain regions from animals aged E16 to adult to determine if the expression of this protein is stable or changes over time. At E16, the levels of Zfp804A mRNA were low in the frontal cortex and cerebellum. Shortly before birth, at E18, the levels increase 3–5 fold, peaking at postnatal day 1 (P1). The mRNA levels dropped again at postnatal day 5 (P5) in the frontal cortex and P3 in cerebellum (Fig 1A and 1B) to levels similar to those found in adult brain. The levels of Zfp804A mRNA are thus significantly increased in E18, P1 and P3 frontal cortex compared to the levels at E16 (P<0.001). In the cerebellum the levels were significantly higher at E18 and P1 compared to E16 (P<0.001). In both the frontal cortex and cerebellum, the levels of Zfp804A mRNA were significantly lower a few days after birth, compared to the peak values at E18 and P1 (P<0.01).

Bottom Line: We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels.Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones.In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

ABSTRACT
A single nucleotide polymorphism in the ZNF804A gene, rs1344706, is associated with schizophrenia. The polymorphism has been suggested to alter fetal expression of ZNF804A. It has also been reported to be associated with altered cortical functioning and neural connectivity in the brain. Since developmental mechanisms are suggested in the pathophysiology for schizophrenia, expression of Zfp804A, the rat homolog of ZNF804A, was investigated in the developing rat brain. We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels. This time point is developmentally the equivalent to the second trimester of fetal development in humans. An exception to this expression pattern is the hippocampus where the expression of Zfp804A appears to increase again in the adult brain. Using laser capture and quantitative PCR we found that Zfp804A mRNA expression in the adult rat hippocampus is highest in the CA1 sub region, where the overall firing rates of neurons is higher than in the CA3 region. In cultured cortical neurons Zfp804A mRNA expression peaked at day 4 and then decreased. The ZFP804A protein expression was therefore investigated with immunochemistry in such cultures. Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones. In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation. We also show that ZFP804A is localized to growth cones of growing neurites. These data implicate ZFP804A in growth cone function and neurite elongation. The polymorphism rs1344706 lowers expression of ZNF804A during prenatal brain development. This may affect ZNF804A's role in cone function and neurite elongation leading to synaptic deficits and altered neural connectivity.

No MeSH data available.


Related in: MedlinePlus