Control of neurulation by the nucleosome assembly protein-1–like 2

Rogner, Ute Christine; Spyropoulos, Demetri D.; Novère, Nicolas Le; Changeux, Jean‐Pierre; Avner, Philip

doi:10.1038/78124

Cited by 82 publications

(84 citation statements)

References 27 publications

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“…The 46C ES cell line was kindly provided by Austin Smith (43). A 10-kb genomic DNA fragment containing the entire Nap1l2 gene was cloned into pBluescript SK(ϩ) (Stratagene) by using the restriction enzymes NotI and XhoI (27). A herpes simplex virus thymidine kinase cassette was inserted into the XhoI site, and a loxP site was inserted into the PmlI site 5Ј of the Nap1l2 promoter.…”

Section: Methodsmentioning

confidence: 99%

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Nap1l2 Promotes Histone Acetylation Activity during Neuronal Differentiation

Attia¹,

Rachez

Pauw³

et al. 2007

Molecular and Cellular Biology

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The deletion of the neuronal Nap1l2 (nucleosome assembly protein 1-like 2) gene in mice causes neural tube defects. We demonstrate here that this phenotype correlates with deficiencies in differentiation and increased maintenance of the neural stem cell stage. Nap1l2 associates with chromatin and interacts with histones H3 and H4. Loss of Nap1l2 results in decreased histone acetylation activity, leading to transcriptional changes in differentiating neurons, which include the marked downregulation of the Cdkn1c (cyclin-dependent kinase inhibitor 1c) gene. Cdkn1c expression normally increases during neuronal differentiation, and this correlates with the specific recruitment of the Nap1l2 protein and an increase in acetylated histone H3K9/14 at the site of Cdkn1c transcription. These results lead us to suggest that the Nap1l2 protein plays an important role in regulating transcription in developing neurons via the control of histone acetylation. Our data support the idea that neuronal nucleosome assembly proteins mediate cell-type-specific mechanisms of establishment/modification of a chromatin-permissive state that can affect neurogenesis and neuronal survival.Mammals possess three neuron-specific nucleosome assembly protein (NAP)-encoding genes, NAP1L2 (29), NAP1L3 (39), and NAP1L5 (37), all of which are both intronless and monoallelically expressed. While the role of the ubiquitously expressed NAPs, NAP1 (NAP1L1) (15,17,19,25,35) and NAP2 (NAP1L4) (14,26), in the assembly of nucleosomes and transport of histones has been extensively characterized, little is known about the role and functioning of neuron-specific NAP1-like proteins.We previously showed that targeted deletion of the murine neuron-specific Nap1l2 (nucleosome assembly protein 1-like 2) gene leads to embryonic lethality from mid-gestation phase onwards, with surviving mutant chimeric embryos showing extensive surface ectoderm defects and open neural tubes similar to those observed in humans with spina bifida and anencephaly. These developmental defects were attributed to the overproliferation of neural precursor cells that is thought to be associated with the absence of Nap1l2 activity (27). The present study aimed to understand the cellular and molecular mechanisms underlying this knockout phenotype.Here we show by ex vivo differentiation studies of embryonic stem (ES) cells from which Nap1l2 was deleted that Nap1l2 regulates the kinetics of neuronal differentiation. In the absence of Nap1l2, neural precursors exhibit a diminished capacity for differentiation, an increase in proliferation, and increased levels of apoptosis. These effects of Nap1l2 deletion are associated with a global decrease in cellular levels of histone acetyltransferase (HAT) activity. This finding is supported by observations that the highly acidic Nap1l2 protein colocalizes to the chromatin in the neuronal nucleus, binds to histones H3 and H4 in vitro, and increases HAT activity. Loss of Nap1l2 results in extensive changes in the transcriptional profile of neural precursor cel...

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Section: Methodsmentioning

confidence: 99%

“…These developmental defects were attributed to the overproliferation of neural precursor cells that is thought to be associated with the absence of Nap1l2 activity (27). The present study aimed to understand the cellular and molecular mechanisms underlying this knockout phenotype.…”

mentioning

confidence: 99%

Nap1l2 Promotes Histone Acetylation Activity during Neuronal Differentiation

Attia¹,

Rachez

Pauw³

et al. 2007

Molecular and Cellular Biology

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“…In Drosophila melanogaster, knocking out NAP1 dramatically reduced viability (Lankenau et al, 2003). In mammals, NAP1 belongs to a multigene family, and the knockout of the mouse neuron-specific NAP1-homolog-2 gene is embryo lethal (Rogner et al, 2000). In plants, NAP1 also belongs to a multigene family (e.g., four genes encoding close NAP1 homologues are present in the genome of Arabidopsis thaliana) (Arabidopsis Genome Initiative, 2000;Dong et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis NRP1andNRP2Encode Histone Chaperones and Are Required for Maintaining Postembryonic Root Growth

et al. 2006

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NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) is conserved from yeast to human and was proposed to act as a histone chaperone. While budding yeast contains a single NAP1 gene, multicellular organisms, including plants and animals, contain several NAP1 and NAP1-RELATED PROTEIN (NRP) genes. However, the biological role of these genes has been largely unexamined. Here, we show that, in Arabidopsis thaliana, simultaneous knockout of the two NRP genes, NRP1 and NRP2, impaired postembryonic root growth. In the nrp1-1 nrp2-1 double mutant, arrest of cell cycle progression at G2/M and disordered cellular organization occurred in root tips. The mutant seedlings exhibit perturbed expression of ;100 genes, including some genes involved in root proliferation and patterning. The mutant plants are highly sensitive to genotoxic stress and show increased levels of DNA damage and the release of transcriptional gene silencing. NRP1 and NRP2 are localized in the nucleus and can form homomeric and heteromeric protein complexes. Both proteins specifically bind histones H2A and H2B and associate with chromatin in vivo. We propose that NRP1 and NRP2 act as H2A/H2B chaperones in the maintenance of dynamic chromatin in epigenetic inheritance.

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“…NAP1 knockout mice have not been generated, and little information is available in mammalian systems to determine whether NAP1 controls the proliferative phenotype. However, inactivation of the NAP1-like 2 gene in mice results in an early gestation (embryonic day 10.5) neural tube defect that is likely due to overproduction of nestin-positive precursor cells (24). In Drosophila melanogaster, NAP1 gene deletion similarly causes early embryonic lethality, although the underlying mechanism has not been determined (18).…”

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confidence: 99%

Regulatory role for nucleosome assembly protein-1 in the proliferative and vasculogenic phenotype of pulmonary endothelium

Clark¹,

Alvarez²,

Alexeyev³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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monary microvascular endothelial cells (PMVECs) are enriched with progenitor cells that underlie their rapid proliferation and vasculogenic capacity. However, the molecular basis for such an enhanced growth potential is unknown. Nucleosome assembly protein-1 (NAP1), and its related family of proteins, have been incriminated in control of cell growth in a range of species. We therefore sought to determine whether NAP1 contributes to the rapid proliferation and vasculogenesis that is observed in PMVECs. NAP1 was expressed at a high level in two fast-growing cell types, including PMVECs and resident microvascular endothelial progenitor cells that were selected from PMVECs, whereas it was expressed at a low level in slowgrowing pulmonary artery endothelial cells (PAECs). Heterologous NAP1 expression increased the growth potential of PAECs, whereas inhibiting NAP1 expression reduced the growth potential of PMVECs. Despite its impact on endothelial cell growth, NAP1 did not influence the expression of endothelial cell-selective markers (PECAM-1, VE-cadherin, von Willebrand factor), and it did not influence cell type-specific lectin binding criterion; PMVECs interact with Griffonia simplicifolia lectin, whereas PAECs interact with Helix pomatia lectin. PMVECs possess a higher basal transelectrical resistance than do PAECs, indicative of their more restrictive barrier property. Changing NAP1 expression did not normalize this basal barrier function between PMVECs and PAECs. To examine whether the growth-promoting actions of NAP1 influence blood vessel formation, endothelial cells were mixed into Matrigel and subcutaneously implanted. PMVECs generated eightfold more blood vessels than did PAECs over a 10-day time course. Heterologous NAP1 expression in PAECs increased the number of blood vessels formed by this cell type, where blood vessel growth approached that seen with PMVECs. Thus, our findings indicate that NAP1 functions as an important regulator of the proliferative and vasculogenic endothelial cell phenotype without globally impacting endothelial cell phenotype specification.angiogenesis; microcirculation; endothelial cells; pulmonary vasculature ENDOTHELIUM LINES ALL BLOOD and lymphatic vessels and separates blood and lymph from the underlying tissue (1, 2, 10). Routine cell turnover is necessary to renew aged and injured endothelium, to ensure cardiovascular health. Estimates from conduit vessels, such as the aorta, suggest that endothelium is renewed every 1-3 years (1, 6). Microvascular endothelial cell turnover has not been similarly measured, although it is evident that pulmonary microvascular endothelial cells (PMVECs) grow at a faster rate, both in vivo and in vitro, than do their macrovascular counterparts (4,17,27). Such an enhanced proliferative potential is due to the extraordinary number of progenitor cells that reside within PMVEC populations (4). These resident microvascular endothelial progenitor cells not only account for the rapid proliferation of microvascular endothelial cells but also underlie...

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Control of neurulation by the nucleosome assembly protein-1–like 2

Cited by 82 publications

References 27 publications

Nap1l2 Promotes Histone Acetylation Activity during Neuronal Differentiation

Nap1l2 Promotes Histone Acetylation Activity during Neuronal Differentiation

Arabidopsis NRP1andNRP2Encode Histone Chaperones and Are Required for Maintaining Postembryonic Root Growth

Regulatory role for nucleosome assembly protein-1 in the proliferative and vasculogenic phenotype of pulmonary endothelium

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