Rnf2 ( Ring1b ) deficiency causes gastrulation arrest and cell cycle inhibition

doi:10.1073/pnas.0434312100

Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition

^*Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; ^‡Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands; and ^¶Institute of Clinical Pathology, University Hospital, CH-8091 Zürich, Switzerland

Edited by Stanley J. Korsmeyer, Dana–Farber Cancer Institute, Boston, MA, and approved December 23, 2002 (received for review July 19, 2002)

Abstract

The highly homologous Rnf2 (Ring1b) and Ring1 (Ring1a) proteins were identified as in vivo interactors of the Polycomb Group (PcG) protein Bmi1. Functional ablation of Rnf2 results in gastrulation arrest, in contrast to relatively mild phenotypes in most other PcG gene null mutants belonging to the same functional group, among which is Ring1. Developmental defects occur in both embryonic and extraembryonic tissues during gastrulation. The early lethal phenotype is reminiscent of that of the PcG-gene knockouts Eed and Ezh2, which belong to a separate functional PcG group and PcG protein complex. This finding indicates that these biochemically distinct PcG complexes are both required during early mouse development. In contrast to the strong skeletal transformation in Ring1 hemizygous mice, hemizygocity for Rnf2 does not affect vertebral identity. However, it does aggravate the cerebellar phenotype in a Bmi1 null-mutant background. Together, these results suggest that Rnf2 or Ring1-containing PcG complexes have minimal functional redundancy in specific tissues, despite overlap in expression patterns. We show that the early developmental arrest in Rnf2-null embryos is partially bypassed by genetic inactivation of the Cdkn2a (Ink4a/ARF) locus. Importantly, this finding implicates Polycomb-mediated repression of the Cdkn2a locus in early murine development.

Footnotes

↵ † Present address: Department of Molecular Genetics, University of Maastricht, 6200 MD, The Netherlands.
↵ § Present address: Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
↵ ‖ To whom correspondence should be addressed. E-mail: m.v.lohuizen{at}nki.nl.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

PcG,

Polycomb Group;

ES cell,

embryonic stem cell;

En,

embryonic day n;

KO,

knockout;

dKO,

double KO;

HE,

heterozygous;

TAP,

tandem affinity purification;

HA,

hemagglutinin