Peri-implantation lethality in mice lacking the Sm motif-containing protein Lsm4

Small nuclear ribonucleoproteins (snRNPs) are particles present only in euk aryotic cells. They are involved in a large variety of RNA maturation proce sses, most notably in pre-mRNA splicing. Several of the proteins typically found in snRNPs contain a sequence signature, the Sm domain, conserved from yeast to mammals. By using a promoter trap strategy to target actively tra nscribed loci in murine embryonic stem cells, a new murine gene encoding an Sm motif-containing protein was identified. Database searches revealed tha t it is the mouse orthologue of Lsm4p, a protein found in yeast and human c ells and putatively associated with U6 snRNA. Introduction of the geo repor ter gene cassette under the control of the murine Lsm4 (mLsm4) endogenous p romoter showed that the gene was ubiquitously transcribed in embryonic and adult tissues. The insertion of the geo cassette disrupted the mLsm4 allele , and homozygosity for the mutation led to a recessive embryonic lethal phe notype. mLsm4-null zygotes survived to the blastocyst stages, implanted int o the uterus, but died shortly thereafter. The early death of mLsm4p-null m ice suggests that the role of mLsm4p in splicing is essential and cannot be compensated by other Lsm proteins.