New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome

Hum Mol Genet. 2014 Mar 15;23(6):1506-15. doi: 10.1093/hmg/ddt537. Epub 2013 Nov 7.

Abstract

Lamins A and C (products of the LMNA gene) are found in roughly equal amounts in peripheral tissues, but the brain produces mainly lamin C and little lamin A. In HeLa cells and fibroblasts, the expression of prelamin A (the precursor to lamin A) can be reduced by miR-9, but the relevance of those cell culture studies to lamin A regulation in the brain was unclear. To address this issue, we created two new Lmna knock-in alleles, one (Lmna(PLAO-5NT)) with a 5-bp mutation in a predicted miR-9 binding site in prelamin A's 3' UTR, and a second (Lmna(PLAO-UTR)) in which prelamin A's 3' UTR was replaced with lamin C's 3' UTR. Neither allele had significant effects on lamin A levels in peripheral tissues; however, both substantially increased prelamin A transcript levels and lamin A protein levels in the cerebral cortex and the cerebellum. The increase in lamin A expression in the brain was more pronounced with the Lmna(PLAO-UTR) allele than with the Lmna(PLAO-5NT) allele. With both alleles, the increased expression of prelamin A transcripts and lamin A protein was greater in the cerebral cortex than in the cerebellum. Our studies demonstrate the in vivo importance of prelamin A's 3' UTR and its miR-9 binding site in regulating lamin A expression in the brain. The reduced expression of prelamin A in the brain likely explains why children with Hutchinson-Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Alleles
  • Animals
  • Cerebellum / metabolism*
  • Cerebral Cortex / metabolism*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Lamin Type A / genetics
  • Lamin Type A / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mutation
  • Nuclear Proteins / genetics*
  • Progeria / genetics*
  • Progeria / metabolism
  • Progeria / pathology
  • Protein Precursors / genetics*

Substances

  • 3' Untranslated Regions
  • Lamin Type A
  • Lmna protein, mouse
  • MIRN9 microRNA, mouse
  • MicroRNAs
  • Nuclear Proteins
  • Protein Precursors
  • prelamin A