title: Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition.
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 (Ink4aARF) locus. Importantly, this finding implicates Polycomb-mediated repression of the Cdkn2a locus in early murine development.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Voncken
authors.forename: Bernard A J
authors.initials: BA
authors.lastname: Roelen
authors.forename: Mieke
authors.initials: M
authors.lastname: Roefs
authors.forename: Stijn
authors.initials: S
authors.lastname: de Vries
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeven
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Deschamps
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism; D019556:COS Cells; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005775:Gastrula; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D016678:Genome; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D063150:Polycomb Repressive Complex 1; D011233:Precipitin Tests; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018076:DNA, Complementary; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1