title: New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome.
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.
authors.affiliation: Molecular Biology Institute.
authors.forename: Hea-Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Yiping
authors.initials: Y
authors.lastname: Tu
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Angelica
authors.initials: A
authors.lastname: Tatar
authors.forename: Chika
authors.initials: C
authors.lastname: Nobumori
authors.forename: Daniel
authors.initials: D
authors.lastname: Wu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
mesh_terms: D020413:3' Untranslated Regions; D000483:Alleles; D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D034904:Lamin Type A; C576142:Lmna protein, mouse; C551804:MIRN9 microRNA, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A