International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany

Plenary Presentations * Oral Presentations *
Poster Presentations: Behavioural Genetics and Genomics * Development and Stem Cells * Functional Genome Analysis * Mouse Models of Human Disease * Mouse System Biology Bioinformatics * Multigenic and Multifactorial Trait Analysis * Nutrition and Metabolic Disease * Phenotyping Methods Imaging * The Genetics and Genomics of Infectious Disease *
Verne Chapman Memorial Lecture * Table of Contents * Sponsor/Exhibitor List * Awards * Photographs

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ORAL PRESENTATION

TUESDAY 11 NOVEMBER
10:00 – 10:15 HRS

UTILISING THE P57^KIP2 KNOCKOUT MOUSE TO UNDERSTAND CELL GROWTH PERTURBATION IN BECKWITH – WIEDEMANN SYNDROME

Lamprill E F
Dept of Anatomy University of Cambridge

Co-Authors: 1) Digger K, 2) Miller N, 3) Barton S C, 4) John R M, 3) Surani A, 1) Schofield P N
Institutions: 1) Dept of Anatomy University of Cambridge, 2) Dept. of Pathology University of Cambridge, 3) Wellcome Trust/CRUK Institute of Developmental Biology and Cancer Cambridge, 4) Imperial College of Science Technology and Medicine London

Cdkn1c is a maternally expressed gene lying within an imprinted cluster on the distal portion of mouse chromosome 7. It encodes the cyclin dependent kinase inhibitor p57^Kip2, which is widely expressed during development and is involved in the regulation of cell proliferation and differentiation. CDKN1C is mutated in some patients with the human overgrowth disorder Beckwith-Wiedemann Syndrome (BWS), implicating the gene in the global regulation of embryonic growth. Interestingly, closely related phenotypes are generated by genetic and epigenetic lesions in IGF2, H19 and KCNQ1OT1 suggesting that several loci or their gene products may be involved in a common rate limiting pathway governing embryonic growth. A mouse cdkn1c knockout model supports this hypothesis (Zhang, et al., (1997) Nature 387, 151) exhibiting a phenotype that shares many features with the human syndrome. We have analysed cell proliferation in mouse embryos and primary embryonic fibroblasts lacking a functional p57^Kip2 gene. Our initial findings suggest that cells lacking p57^Kip2 derived from E14.5 knockout embryos show marked insensitivity to density dependent growth inhibition. FACS analysis in whole embryos from E10.5-E15.5 shows subtle shifts in cell cycle parameters during embryonic development. BWS patient fibroblasts have been used to complement this approach, and whilst we have been unable to detect changes in cell cycle kinetics thus far, differences in the onset of cellular senescence onset have been identified when compared to normal controls. The implications of these findings for both the normal role of p57^Kip2 in development and when it is dysregulated will be discussed.