title: Deregulation of the p57-E2F1-p53 axis results in nonobstructive hydrocephalus and cerebellar malformation in mice.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Etsuo
authors.initials: E
authors.lastname: Susaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Mikio
authors.initials: M
authors.lastname: Hoshino
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051762:PAX2 Transcription Factor / Q000032:analysis / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27