Deregulation of the p57-E2F1-p53 axis results in nonobstructive hydrocephalus and cerebellar malformation in mice

Akinobu Matsumoto, Etsuo Susaki, Ichiro Onoyama, Keiko Nakayama, Mikio Hoshino, Keiichi I. Nakayama

研究成果: ジャーナルへの寄稿記事

11 引用 (Scopus)

抄録

The cyclin-dependent kinase inhibitor (CKI) p57 Kip2 plays a pivotal role in cell cycle arrest during development, in particular, in the regulation of the entry of proliferating progenitors into quiescence. The gene encoding p57 undergoes genomic imprinting, and impairment of the regulation of p57 expression results in various developmental anomalies in humans and mice. We now show that p57 is expressed predominantly in the subcommissural organ and cerebellar interneurons in the mouse brain and that mice with brain-specific deletion of the p57 gene (Kip2) manifest prominent nonobstructive hydrocephalus as well as cerebellar malformation associated with the loss of Pax2-positive interneuron precursors and their descendants, including Golgi cells and γ-aminobutyric acid-containing neurons of the deep cerebellar nuclei. These abnormalities were found to be attributable to massive apoptosis of precursor cells in the developing brain. The morphological defects of the p57-deficient mice were corrected by knock-in of the gene for the related CKI p27 Kip1 at the Kip2 locus. The abnormalities were also prevented by additional genetic ablation of p53 or E2F1. Our results thus implicate p57 in cell cycle arrest in the subcommissural organ and Pax2-positive interneuron precursors, with the lack of p57 resulting in induction of p53-dependent apoptosis due to hyperactivation of E2F1.

元の言語英語
ページ(範囲)4176-4192
ページ数17
ジャーナルMolecular and cellular biology
31
発行部数20
DOI
出版物ステータス出版済み - 10 1 2011

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Hydrocephalus
Interneurons
Subcommissural Organ
Cell Cycle Checkpoints
Cyclin-Dependent Kinase Inhibitor p57
Gene Knock-In Techniques
Brain
Cyclin-Dependent Kinase Inhibitor p27
Apoptosis
Genomic Imprinting
Aminobutyrates
Cerebellar Nuclei
Gene Deletion
Neurons
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

これを引用

Deregulation of the p57-E2F1-p53 axis results in nonobstructive hydrocephalus and cerebellar malformation in mice. / Matsumoto, Akinobu; Susaki, Etsuo; Onoyama, Ichiro; Nakayama, Keiko; Hoshino, Mikio; Nakayama, Keiichi I.

:: Molecular and cellular biology, 巻 31, 番号 20, 01.10.2011, p. 4176-4192.

研究成果: ジャーナルへの寄稿記事

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abstract = "The cyclin-dependent kinase inhibitor (CKI) p57 Kip2 plays a pivotal role in cell cycle arrest during development, in particular, in the regulation of the entry of proliferating progenitors into quiescence. The gene encoding p57 undergoes genomic imprinting, and impairment of the regulation of p57 expression results in various developmental anomalies in humans and mice. We now show that p57 is expressed predominantly in the subcommissural organ and cerebellar interneurons in the mouse brain and that mice with brain-specific deletion of the p57 gene (Kip2) manifest prominent nonobstructive hydrocephalus as well as cerebellar malformation associated with the loss of Pax2-positive interneuron precursors and their descendants, including Golgi cells and γ-aminobutyric acid-containing neurons of the deep cerebellar nuclei. These abnormalities were found to be attributable to massive apoptosis of precursor cells in the developing brain. The morphological defects of the p57-deficient mice were corrected by knock-in of the gene for the related CKI p27 Kip1 at the Kip2 locus. The abnormalities were also prevented by additional genetic ablation of p53 or E2F1. Our results thus implicate p57 in cell cycle arrest in the subcommissural organ and Pax2-positive interneuron precursors, with the lack of p57 resulting in induction of p53-dependent apoptosis due to hyperactivation of E2F1.",
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