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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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Defective Tbr2+ and NeuroD1+ neuronal precursors in the mutant hippocampus.(A-D) Immunostaining to detect Tbr2+ intermediate neuronal progenitors on sections from E13.5, E16.5, P0 and P10 brains. At E13.5 (A), Tbr2 was similarly expressed in the control and mutant neuroepithelium and hippocampus primordium (HP). At E16.5 (B), Tbr2 was similarly expressed in the control and mutant subventricular zones (SVZ) and hippocampi. At P0 and P10, there were fewer Tbr2+ progenitors in the mutant dentate gyrus (C-D). The yellow arrowheads in the right two panels mark four progenitors that failed to settle in the subgranular zone, but stayed at the outer rim of the molecular cell layer. (E) Quantification of Tbr2+ progenitors in the developing dentate gyrus at P0, outlined with clear dash lines in (C). While there was no significant difference in the cell density (right), the Tbr2+ progenitor number per section decreased significantly in the mutant (left). The quantification was based on three pairs of control and mutant brains, with at least three matched sections per brain. **p<0.01; ns, not statistically significant. (F-H) Immunofluorescence microscopy to detect NeuroD1+ neuroblasts on E16.5, P10 and P24 brain sections. At E16.5 (F), NeuroD1 expression was relatively normal in the mutant hippocampus (HP), but it virtually disappeared in the mutant dentate gyrus at P10 (G) and P24 (H). DG, dentate gyrus; dNE, dentate neuroepithelium; dms, dentate migration stream; HP, hippocampus; sb, suprapyramidal blade; ib, infrapyramidal blade; SVZ, subventricular zone; scale bars, 100 μm.
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pgen.1005034.g006: Defective Tbr2+ and NeuroD1+ neuronal precursors in the mutant hippocampus.(A-D) Immunostaining to detect Tbr2+ intermediate neuronal progenitors on sections from E13.5, E16.5, P0 and P10 brains. At E13.5 (A), Tbr2 was similarly expressed in the control and mutant neuroepithelium and hippocampus primordium (HP). At E16.5 (B), Tbr2 was similarly expressed in the control and mutant subventricular zones (SVZ) and hippocampi. At P0 and P10, there were fewer Tbr2+ progenitors in the mutant dentate gyrus (C-D). The yellow arrowheads in the right two panels mark four progenitors that failed to settle in the subgranular zone, but stayed at the outer rim of the molecular cell layer. (E) Quantification of Tbr2+ progenitors in the developing dentate gyrus at P0, outlined with clear dash lines in (C). While there was no significant difference in the cell density (right), the Tbr2+ progenitor number per section decreased significantly in the mutant (left). The quantification was based on three pairs of control and mutant brains, with at least three matched sections per brain. **p<0.01; ns, not statistically significant. (F-H) Immunofluorescence microscopy to detect NeuroD1+ neuroblasts on E16.5, P10 and P24 brain sections. At E16.5 (F), NeuroD1 expression was relatively normal in the mutant hippocampus (HP), but it virtually disappeared in the mutant dentate gyrus at P10 (G) and P24 (H). DG, dentate gyrus; dNE, dentate neuroepithelium; dms, dentate migration stream; HP, hippocampus; sb, suprapyramidal blade; ib, infrapyramidal blade; SVZ, subventricular zone; scale bars, 100 μm.

Mentions: We next analyzed intermediate neuronal progenitors with an anti-Tbr2 antibody. At E13.5, Tbr2 expression in the hippocampal primordium was rather similar between the wild-type and mutant (Fig. 6A). By E16.5, Tbr2+ progenitors were present in the wild-type dentate neuroepithelium and migrated along the dentate migratory stream to the forming dentate gyrus (Fig. 6B, left two panels). Such migration was also found in the mutant, but the population was smaller in the forming dentate gyrus (Fig. 6B, right two panels). At P0, a similar difference was found between the wild-type and mutant dentate gyri (Fig. 6C). Quantification confirmed this (Fig. 6E). As the development progressed, Tbr2+ progenitors translocated to the subgranular zone and the hilum of the wild-type dentate gyrus (Fig. 6D, left two panels). In stark contrast, no such translocation was found in the mutant (right two panels), with some of Tbr2+ progenitors stayed at the molecular cell layer (Fig. 6D, right two panels; marked with yellow arrowheads). These results indicate that the abnormalities start at a fetal stage and Brpf1 inactivation impairs the migration of Tbr2+ progenitors.


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)

Defective Tbr2+ and NeuroD1+ neuronal precursors in the mutant hippocampus.(A-D) Immunostaining to detect Tbr2+ intermediate neuronal progenitors on sections from E13.5, E16.5, P0 and P10 brains. At E13.5 (A), Tbr2 was similarly expressed in the control and mutant neuroepithelium and hippocampus primordium (HP). At E16.5 (B), Tbr2 was similarly expressed in the control and mutant subventricular zones (SVZ) and hippocampi. At P0 and P10, there were fewer Tbr2+ progenitors in the mutant dentate gyrus (C-D). The yellow arrowheads in the right two panels mark four progenitors that failed to settle in the subgranular zone, but stayed at the outer rim of the molecular cell layer. (E) Quantification of Tbr2+ progenitors in the developing dentate gyrus at P0, outlined with clear dash lines in (C). While there was no significant difference in the cell density (right), the Tbr2+ progenitor number per section decreased significantly in the mutant (left). The quantification was based on three pairs of control and mutant brains, with at least three matched sections per brain. **p<0.01; ns, not statistically significant. (F-H) Immunofluorescence microscopy to detect NeuroD1+ neuroblasts on E16.5, P10 and P24 brain sections. At E16.5 (F), NeuroD1 expression was relatively normal in the mutant hippocampus (HP), but it virtually disappeared in the mutant dentate gyrus at P10 (G) and P24 (H). DG, dentate gyrus; dNE, dentate neuroepithelium; dms, dentate migration stream; HP, hippocampus; sb, suprapyramidal blade; ib, infrapyramidal blade; SVZ, subventricular zone; scale bars, 100 μm.
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pgen.1005034.g006: Defective Tbr2+ and NeuroD1+ neuronal precursors in the mutant hippocampus.(A-D) Immunostaining to detect Tbr2+ intermediate neuronal progenitors on sections from E13.5, E16.5, P0 and P10 brains. At E13.5 (A), Tbr2 was similarly expressed in the control and mutant neuroepithelium and hippocampus primordium (HP). At E16.5 (B), Tbr2 was similarly expressed in the control and mutant subventricular zones (SVZ) and hippocampi. At P0 and P10, there were fewer Tbr2+ progenitors in the mutant dentate gyrus (C-D). The yellow arrowheads in the right two panels mark four progenitors that failed to settle in the subgranular zone, but stayed at the outer rim of the molecular cell layer. (E) Quantification of Tbr2+ progenitors in the developing dentate gyrus at P0, outlined with clear dash lines in (C). While there was no significant difference in the cell density (right), the Tbr2+ progenitor number per section decreased significantly in the mutant (left). The quantification was based on three pairs of control and mutant brains, with at least three matched sections per brain. **p<0.01; ns, not statistically significant. (F-H) Immunofluorescence microscopy to detect NeuroD1+ neuroblasts on E16.5, P10 and P24 brain sections. At E16.5 (F), NeuroD1 expression was relatively normal in the mutant hippocampus (HP), but it virtually disappeared in the mutant dentate gyrus at P10 (G) and P24 (H). DG, dentate gyrus; dNE, dentate neuroepithelium; dms, dentate migration stream; HP, hippocampus; sb, suprapyramidal blade; ib, infrapyramidal blade; SVZ, subventricular zone; scale bars, 100 μm.
Mentions: We next analyzed intermediate neuronal progenitors with an anti-Tbr2 antibody. At E13.5, Tbr2 expression in the hippocampal primordium was rather similar between the wild-type and mutant (Fig. 6A). By E16.5, Tbr2+ progenitors were present in the wild-type dentate neuroepithelium and migrated along the dentate migratory stream to the forming dentate gyrus (Fig. 6B, left two panels). Such migration was also found in the mutant, but the population was smaller in the forming dentate gyrus (Fig. 6B, right two panels). At P0, a similar difference was found between the wild-type and mutant dentate gyri (Fig. 6C). Quantification confirmed this (Fig. 6E). As the development progressed, Tbr2+ progenitors translocated to the subgranular zone and the hilum of the wild-type dentate gyrus (Fig. 6D, left two panels). In stark contrast, no such translocation was found in the mutant (right two panels), with some of Tbr2+ progenitors stayed at the molecular cell layer (Fig. 6D, right two panels; marked with yellow arrowheads). These results indicate that the abnormalities start at a fetal stage and Brpf1 inactivation impairs the migration of Tbr2+ progenitors.

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