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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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Brpf1 loss impairs dentate gyrus development, dendritic tree formation and neuronal proliferation.(A-B) Nissl staining of coronal brain sections from E17.5 and P0 mice. At P0, loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the developing dentate gyrus. (C) Golgi-Cox staining of coronal brain sections at P19. Representative images of hippocampal regions from the wild-type and bKO brain sections show that the bKO hippocampus possessed disorganized neurons, with less robust dendritic trees. There were also fewer neurons in the mutant dentate gyrus. Red asterisks denote areas accidentally torn during staining. The boxed regions in the top panels are shown in the lower panels at higher magnification. (D-E) Ki67 immunohistochemistry showing that cell proliferation dramatically decreased in the subgranular zone of the bKO dentate gyrus at P10 and P24. The subgranular zones of the control P10 and P24 sections shown here contain 20 and 34 Ki67+ cells, respectively, whereas the corresponding regions of the mutant sections possess either one or no Ki67+ cells. Scale bars, 100 μm for (A-B & D-E) and 200 μm for (C).
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pgen.1005034.g003: Brpf1 loss impairs dentate gyrus development, dendritic tree formation and neuronal proliferation.(A-B) Nissl staining of coronal brain sections from E17.5 and P0 mice. At P0, loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the developing dentate gyrus. (C) Golgi-Cox staining of coronal brain sections at P19. Representative images of hippocampal regions from the wild-type and bKO brain sections show that the bKO hippocampus possessed disorganized neurons, with less robust dendritic trees. There were also fewer neurons in the mutant dentate gyrus. Red asterisks denote areas accidentally torn during staining. The boxed regions in the top panels are shown in the lower panels at higher magnification. (D-E) Ki67 immunohistochemistry showing that cell proliferation dramatically decreased in the subgranular zone of the bKO dentate gyrus at P10 and P24. The subgranular zones of the control P10 and P24 sections shown here contain 20 and 34 Ki67+ cells, respectively, whereas the corresponding regions of the mutant sections possess either one or no Ki67+ cells. Scale bars, 100 μm for (A-B & D-E) and 200 μm for (C).

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)

Brpf1 loss impairs dentate gyrus development, dendritic tree formation and neuronal proliferation.(A-B) Nissl staining of coronal brain sections from E17.5 and P0 mice. At P0, loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the developing dentate gyrus. (C) Golgi-Cox staining of coronal brain sections at P19. Representative images of hippocampal regions from the wild-type and bKO brain sections show that the bKO hippocampus possessed disorganized neurons, with less robust dendritic trees. There were also fewer neurons in the mutant dentate gyrus. Red asterisks denote areas accidentally torn during staining. The boxed regions in the top panels are shown in the lower panels at higher magnification. (D-E) Ki67 immunohistochemistry showing that cell proliferation dramatically decreased in the subgranular zone of the bKO dentate gyrus at P10 and P24. The subgranular zones of the control P10 and P24 sections shown here contain 20 and 34 Ki67+ cells, respectively, whereas the corresponding regions of the mutant sections possess either one or no Ki67+ cells. Scale bars, 100 μm for (A-B & D-E) and 200 μm for (C).
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pgen.1005034.g003: Brpf1 loss impairs dentate gyrus development, dendritic tree formation and neuronal proliferation.(A-B) Nissl staining of coronal brain sections from E17.5 and P0 mice. At P0, loss of Brpf1 resulted in underdevelopment of the suprapyramidal blade (sb) and disappearance of the infrapyramidal blade (ib) in the developing dentate gyrus. (C) Golgi-Cox staining of coronal brain sections at P19. Representative images of hippocampal regions from the wild-type and bKO brain sections show that the bKO hippocampus possessed disorganized neurons, with less robust dendritic trees. There were also fewer neurons in the mutant dentate gyrus. Red asterisks denote areas accidentally torn during staining. The boxed regions in the top panels are shown in the lower panels at higher magnification. (D-E) Ki67 immunohistochemistry showing that cell proliferation dramatically decreased in the subgranular zone of the bKO dentate gyrus at P10 and P24. The subgranular zones of the control P10 and P24 sections shown here contain 20 and 34 Ki67+ cells, respectively, whereas the corresponding regions of the mutant sections possess either one or no Ki67+ cells. Scale bars, 100 μm for (A-B & D-E) and 200 μm for (C).
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