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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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Forebrain-specific Brpf1 loss causes hypoplasia of the dentate gyrus.(A-B) Nissl staining was performed on coronal brain sections from P10 and P24 mice. Loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the dentate gyrus. The border between cornu ammonis 1 (CA1) and the subiculum (SB) was clearly defined in the wild-type sections but became obscure in the mutant, as indicated by red arrowheads in (A). At P10 and P24, the pyramidal layers of CA1 and CA3 in the mutant sections were not as tightly packed as in the wild-type (A-B). (C-D) Nissl staining of serial brain sections. Five medial-to-lateral sagittal sections were prepared from P10 (C) or P24 (D) wild-type and mutant brains and Nissl-stained to analyze the morphology of the hippocampus at different planes (A). The border between CA1 and the subiculum, marked by red arrowheads, was clearly defined in the wild-type but not mutant sections. v, ventral hippocampus; d, dorsal hippocampus. Scale bars, 100 μm for (A-B) and 0.5 mm for (C-D).
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pgen.1005034.g002: Forebrain-specific Brpf1 loss causes hypoplasia of the dentate gyrus.(A-B) Nissl staining was performed on coronal brain sections from P10 and P24 mice. Loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the dentate gyrus. The border between cornu ammonis 1 (CA1) and the subiculum (SB) was clearly defined in the wild-type sections but became obscure in the mutant, as indicated by red arrowheads in (A). At P10 and P24, the pyramidal layers of CA1 and CA3 in the mutant sections were not as tightly packed as in the wild-type (A-B). (C-D) Nissl staining of serial brain sections. Five medial-to-lateral sagittal sections were prepared from P10 (C) or P24 (D) wild-type and mutant brains and Nissl-stained to analyze the morphology of the hippocampus at different planes (A). The border between CA1 and the subiculum, marked by red arrowheads, was clearly defined in the wild-type but not mutant sections. v, ventral hippocampus; d, dorsal hippocampus. Scale bars, 100 μm for (A-B) and 0.5 mm for (C-D).

Mentions: Nissl staining of brain sections revealed that when compared to the control, the suprapyramidal blade of the dorsal hippocampus in the P10 mutant brain was shorter, with one end remaining attached to the ventricular zone, whereas the infrapyramidal blade was completely missing (Fig. 2A, right). The nuclear layers of CA1 and CA3 appeared more diffusely packed than those in the control (Fig. 2A, right). In the mutant, the junction of CA1 with the subiculum was not as clear-cut as that in the control and the subiculum itself was expanded. Similar changes were found in the mutant brain at P24 (Fig. 2B). More importantly, these defects also appeared in serial sagittal sections and similar abnormalities were found in the ventral hippocampus (Fig. 2C-D), indicating that the entire hippocampal formation is affected. The mouse dentate gyrus develops from the cortical hem around mid-gestation and involves dynamic neuron migration and differentiation, both of which continue in the first two weeks after birth [58,59]. To determine the developmental point when the defects start to occur, we applied Nissl staining to brain sections from E17.5 fetuses and P0 neonates. As shown in Fig. 3A-B, the developing dentate gyrus was underdeveloped at both time points, indicating that the defects originate from prenatal development.


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)

Forebrain-specific Brpf1 loss causes hypoplasia of the dentate gyrus.(A-B) Nissl staining was performed on coronal brain sections from P10 and P24 mice. Loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the dentate gyrus. The border between cornu ammonis 1 (CA1) and the subiculum (SB) was clearly defined in the wild-type sections but became obscure in the mutant, as indicated by red arrowheads in (A). At P10 and P24, the pyramidal layers of CA1 and CA3 in the mutant sections were not as tightly packed as in the wild-type (A-B). (C-D) Nissl staining of serial brain sections. Five medial-to-lateral sagittal sections were prepared from P10 (C) or P24 (D) wild-type and mutant brains and Nissl-stained to analyze the morphology of the hippocampus at different planes (A). The border between CA1 and the subiculum, marked by red arrowheads, was clearly defined in the wild-type but not mutant sections. v, ventral hippocampus; d, dorsal hippocampus. Scale bars, 100 μm for (A-B) and 0.5 mm for (C-D).
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Related In: Results  -  Collection

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pgen.1005034.g002: Forebrain-specific Brpf1 loss causes hypoplasia of the dentate gyrus.(A-B) Nissl staining was performed on coronal brain sections from P10 and P24 mice. Loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the dentate gyrus. The border between cornu ammonis 1 (CA1) and the subiculum (SB) was clearly defined in the wild-type sections but became obscure in the mutant, as indicated by red arrowheads in (A). At P10 and P24, the pyramidal layers of CA1 and CA3 in the mutant sections were not as tightly packed as in the wild-type (A-B). (C-D) Nissl staining of serial brain sections. Five medial-to-lateral sagittal sections were prepared from P10 (C) or P24 (D) wild-type and mutant brains and Nissl-stained to analyze the morphology of the hippocampus at different planes (A). The border between CA1 and the subiculum, marked by red arrowheads, was clearly defined in the wild-type but not mutant sections. v, ventral hippocampus; d, dorsal hippocampus. Scale bars, 100 μm for (A-B) and 0.5 mm for (C-D).
Mentions: Nissl staining of brain sections revealed that when compared to the control, the suprapyramidal blade of the dorsal hippocampus in the P10 mutant brain was shorter, with one end remaining attached to the ventricular zone, whereas the infrapyramidal blade was completely missing (Fig. 2A, right). The nuclear layers of CA1 and CA3 appeared more diffusely packed than those in the control (Fig. 2A, right). In the mutant, the junction of CA1 with the subiculum was not as clear-cut as that in the control and the subiculum itself was expanded. Similar changes were found in the mutant brain at P24 (Fig. 2B). More importantly, these defects also appeared in serial sagittal sections and similar abnormalities were found in the ventral hippocampus (Fig. 2C-D), indicating that the entire hippocampal formation is affected. The mouse dentate gyrus develops from the cortical hem around mid-gestation and involves dynamic neuron migration and differentiation, both of which continue in the first two weeks after birth [58,59]. To determine the developmental point when the defects start to occur, we applied Nissl staining to brain sections from E17.5 fetuses and P0 neonates. As shown in Fig. 3A-B, the developing dentate gyrus was underdeveloped at both time points, indicating that the defects originate from prenatal development.

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