Post-natal myogenic and adipogenic developmental

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 postnatal 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 postnatal development critically contributes to the disease phenotypes in adult laminopathies. Post-natal myogenic and adipogenic developmentalDefects and metabolic impairment upon loss of A-type lamins myocytes, skeletal muscle hypotrophy, decreased subcutaneous adipose tissue deposits, decreased adipogenic differentiation of MEFs and metabolic derangements. Ultimately these tissue differentiation and maturation defects are lethal before mice are weaned. These results demonstrate that lamin A/C is crucial in the early post-natal period and they provide novel insights into the physiological function of A-type lamins in the context of the developing animal.

Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation

“…5K). Ectopic bone with MSC grafts has been found to be inhibited by RA and a RARG-specific agonist (57, 58), and RARG knockout mice also exhibit osteochondral defects and live only weeks longer than the few weeks that LMNA- deficient mice survive (59–61). Chromatin-IP has thus far identified the RUNX2 gene to be a target of RA transcription factors but not yet SRF (fig.…”

“…LMNA knockout mice develop all tissues but die weeks after birth with growth retardation of connective tissues and also muscular dystrophy (59–61) that is very severe compared with the prototypical mouse model of muscular dystrophy ( Dmd mdx ), which lives for 2 years (76). LMNA expression is therefore essential for maturation and survival against the incessant stressing in adult tissues, and once the lamin level matches to the stress, then the optimal level can enhance a prespecified lineage.…”

Targeting Mitogen-Activated Protein Kinase Signaling in Mouse Models of Cardiomyopathy Caused by Lamin A/C Gene Mutations

“…One report has suggested that these mice may not be complete knockouts but rather express a truncated prelamin A ( Jahn et al, 2012). Nonetheless, these mice and embryonic fibroblasts derived from them have been widely used to obtain important insights regarding the functions of lamin A and lamin C. Another gene trap Lmna knockout line has a shorter lifespan and does not develop left ventricular dilatation prior to death (Kubben et al, 2011). …”

Genetic Variations Leading to Familial Dilated Cardiomyopathy

“…Interestingly, an independent study showed that Lmna +/− mice develop severe cardiac abnormalities at 12 months of age analogous to those in humans with LMNA -mediated DCM (Wolf et al, 2008). Kubben et al created the Lmna GT/GT mouse model to study loss of function of Lmna (Kubben et al, 2011). Lmna GT/GT mice were created by placing a gene trap cassette between exon 1C and exon 2 of Lmna , which introduced the Lmna exon 1- or exon 1C-β -geo fusion allele.…”