Post-natal myogenic and adipogenic developmental

• DOI: 10.4161/nucl.2.3.15731
• Publication Date: 2011-07-01T18:59:55Z
• Authors: Nard Kubben; Jan Willem Voncken; Gonda Konings; Michel van Weeghel; Maarten M.G. van ...; Marion Gijbels; Arie van Erk; Kees Schoonderwoerd; Bianca van den Bosch; Vivian Dahlmans; Chantal Calis; Sander M. Houten; Tom Misteli; Yigal M. Pinto
• Keywords: Male; 0301 basic medicine; Adipogenesis; Subcutaneous Fat; Embryonic Development; Hypertrophy; Fibroblasts; Lamin Type A; Muscle Development; Mice; 03 medical and health sciences; Phenotype; Metabolic Diseases; Genes, Reporter; Animals; Myocytes, Cardiac; Muscle, Skeletal; Promoter Regions, Genetic; Transcriptome; EMC MGC-02-96-01; Gene Deletion

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.