Post-natal myogenic and adipogenic developmental: defects and metabolic impairment upon loss of A-type lamins

Nucleus. May-Jun 2011;2(3):195-207. doi: 10.4161/nucl.2.3.15731.

Abstract

A-type lamins are a major component of the nuclear lamina. Mutations in the LMNA gene, which encodes the A-type lamins A and C, cause a set of phenotypically diverse diseases collectively called laminopathies. While adult LMNA null mice show various symptoms typically associated with laminopathies, the effect of loss of lamin A/C on early post-natal development is poorly understood. Here we developed a novel LMNA null mouse (LMNA(GT-/-)) based on genetrap technology and analyzed its early post-natal development. We detect LMNA transcripts in heart, the outflow tract, dorsal aorta, liver and somites during early embryonic development. Loss of A-type lamins results in severe growth retardation and developmental defects of the heart, including impaired myocyte hypertrophy, skeletal muscle hypotrophy, decreased amounts of subcutaneous adipose tissue and impaired ex vivo adipogenic differentiation. These defects cause death at 2 to 3 weeks post partum associated with muscle weakness and metabolic complications, but without the occurrence of dilated cardiomyopathy or an obvious progeroid phenotype. Our results indicate that defective early post-natal development critically contributes to the disease phenotypes in adult laminopathies.

Keywords: LMNA; cardiac hypertrophy; differentiation; knock-out mouse; lamin A; laminopathies; muscular dystrophy.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / genetics*
  • Animals
  • Embryonic Development / genetics
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Deletion*
  • Genes, Reporter / genetics
  • Hypertrophy / genetics
  • Lamin Type A / deficiency*
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism*
  • Metabolic Diseases / pathology*
  • Metabolic Diseases / physiopathology
  • Mice
  • Muscle Development / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Subcutaneous Fat / metabolism
  • Subcutaneous Fat / pathology
  • Transcriptome

Substances

  • Lamin Type A