RACK1 depletion in a mouse model causes lethality, pigmentation deficits and reduction in protein synthesis efficiency

Cell Mol Life Sci. 2013 Apr;70(8):1439-50. doi: 10.1007/s00018-012-1215-y. Epub 2012 Dec 2.

Abstract

The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Embryo Loss / genetics
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / ultrastructure
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuropeptides / genetics*
  • Neuropeptides / metabolism
  • Phenotype
  • Pigmentation*
  • Protein Biosynthesis*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors for Activated C Kinase
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Neuropeptides
  • RACK1 protein, mouse
  • RNA, Small Interfering
  • Receptors for Activated C Kinase
  • Tumor Suppressor Protein p53