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The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

You L, Yan K, Zou J, Zhou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ - PLoS Genet. (2015)

Bottom Line: Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively.We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors.These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.

ABSTRACT
Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

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Analysis of neuronal migration in the hippocampus by BrdU labeling.(A-B) After injection with BrdU at E12.5, E14.5 and E16.5, pregnant mice were sacrificed at P0 for immunohistochemical analysis with an anti-BrdU monoclonal antibody. Representative images of the hippocampal regions are shown in (A) and the quantification results of three BrdU+ progenitor populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry), are presented in (B). The tertiary matrix corresponds to the developing dentate gyrus. For each time point, the quantification was based on 2 pairs of control and mutant brains, with 4 or 5 matched sections per brain. (C-D) After injection with BrdU at P12, wild-type and mutant pups were sacrificed 1 h later for immunohistochemical analysis with the anti-BrdU antibody. Representative images of the hippocampal regions are shown in (C) and the quantification result of BrdU+ S-phase cells at the subgranular zone (marked with the yellow dashed lines) is presented in (D). The quantification was based on 2 pairs of control and mutant pups, with 4 matched sections per pup. Scale bars, 200 μm; ns, not statistically significant; **p<0.01; ***p<0.001.
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pgen.1005034.g007: Analysis of neuronal migration in the hippocampus by BrdU labeling.(A-B) After injection with BrdU at E12.5, E14.5 and E16.5, pregnant mice were sacrificed at P0 for immunohistochemical analysis with an anti-BrdU monoclonal antibody. Representative images of the hippocampal regions are shown in (A) and the quantification results of three BrdU+ progenitor populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry), are presented in (B). The tertiary matrix corresponds to the developing dentate gyrus. For each time point, the quantification was based on 2 pairs of control and mutant brains, with 4 or 5 matched sections per brain. (C-D) After injection with BrdU at P12, wild-type and mutant pups were sacrificed 1 h later for immunohistochemical analysis with the anti-BrdU antibody. Representative images of the hippocampal regions are shown in (C) and the quantification result of BrdU+ S-phase cells at the subgranular zone (marked with the yellow dashed lines) is presented in (D). The quantification was based on 2 pairs of control and mutant pups, with 4 matched sections per pup. Scale bars, 200 μm; ns, not statistically significant; **p<0.01; ***p<0.001.

Mentions: At the prenatal and postnatal stages, dentate gyrus development involves two waves of neuronal precursors migrating from the neuroepithelium at the ventricular or subventricular zone to the dentate gyrus [58,59,74,75], so we next investigated whether and how Brpf1 loss affects the migration. For this, BrdU was injected into pregnant dams at E12.5, E14.5 and E16.5. The dams were then sacrificed at P0 to isolate the brain for immunohistochemical analysis with an anti-BrdU monoclonal antibody. BrdU+ cells were quantified as three populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry) (Fig. 7A, top left) [66]. Representative images of the hippocampal regions are shown in Fig. 7A and the quantification results of the three BrdU+ populations are presented in Fig. 7B. In the first and second matrices, no difference was found between the control and mutant for all three labeling time points. In the tertiary matrix (corresponding to the developing dentate gyrus), there were fewer BrdU+ cells when labeled at E12.5 and E14.5 (Fig. 7A-B), indicating that Brpf1 loss affects migration of neuronal progenitors from the dentate neuroepithelium to the developing dentate gyrus.


The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

You L, Yan K, Zou J, Zhou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ - PLoS Genet. (2015)

Analysis of neuronal migration in the hippocampus by BrdU labeling.(A-B) After injection with BrdU at E12.5, E14.5 and E16.5, pregnant mice were sacrificed at P0 for immunohistochemical analysis with an anti-BrdU monoclonal antibody. Representative images of the hippocampal regions are shown in (A) and the quantification results of three BrdU+ progenitor populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry), are presented in (B). The tertiary matrix corresponds to the developing dentate gyrus. For each time point, the quantification was based on 2 pairs of control and mutant brains, with 4 or 5 matched sections per brain. (C-D) After injection with BrdU at P12, wild-type and mutant pups were sacrificed 1 h later for immunohistochemical analysis with the anti-BrdU antibody. Representative images of the hippocampal regions are shown in (C) and the quantification result of BrdU+ S-phase cells at the subgranular zone (marked with the yellow dashed lines) is presented in (D). The quantification was based on 2 pairs of control and mutant pups, with 4 matched sections per pup. Scale bars, 200 μm; ns, not statistically significant; **p<0.01; ***p<0.001.
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pgen.1005034.g007: Analysis of neuronal migration in the hippocampus by BrdU labeling.(A-B) After injection with BrdU at E12.5, E14.5 and E16.5, pregnant mice were sacrificed at P0 for immunohistochemical analysis with an anti-BrdU monoclonal antibody. Representative images of the hippocampal regions are shown in (A) and the quantification results of three BrdU+ progenitor populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry), are presented in (B). The tertiary matrix corresponds to the developing dentate gyrus. For each time point, the quantification was based on 2 pairs of control and mutant brains, with 4 or 5 matched sections per brain. (C-D) After injection with BrdU at P12, wild-type and mutant pups were sacrificed 1 h later for immunohistochemical analysis with the anti-BrdU antibody. Representative images of the hippocampal regions are shown in (C) and the quantification result of BrdU+ S-phase cells at the subgranular zone (marked with the yellow dashed lines) is presented in (D). The quantification was based on 2 pairs of control and mutant pups, with 4 matched sections per pup. Scale bars, 200 μm; ns, not statistically significant; **p<0.01; ***p<0.001.
Mentions: At the prenatal and postnatal stages, dentate gyrus development involves two waves of neuronal precursors migrating from the neuroepithelium at the ventricular or subventricular zone to the dentate gyrus [58,59,74,75], so we next investigated whether and how Brpf1 loss affects the migration. For this, BrdU was injected into pregnant dams at E12.5, E14.5 and E16.5. The dams were then sacrificed at P0 to isolate the brain for immunohistochemical analysis with an anti-BrdU monoclonal antibody. BrdU+ cells were quantified as three populations, outlined as the primary matrix (1ry), secondary matrix (2ry) and tertiary matrix (3ry) (Fig. 7A, top left) [66]. Representative images of the hippocampal regions are shown in Fig. 7A and the quantification results of the three BrdU+ populations are presented in Fig. 7B. In the first and second matrices, no difference was found between the control and mutant for all three labeling time points. In the tertiary matrix (corresponding to the developing dentate gyrus), there were fewer BrdU+ cells when labeled at E12.5 and E14.5 (Fig. 7A-B), indicating that Brpf1 loss affects migration of neuronal progenitors from the dentate neuroepithelium to the developing dentate gyrus.

Bottom Line: Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively.We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors.These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.

ABSTRACT
Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

Show MeSH
Related in: MedlinePlus