Postnatal development of mice with combined genetic depletions of lamin A/C, emerin and lamina-associated polypeptide 1

Abstract

Mutations in LMNA encoding lamin A/C and EMD encoding emerin cause cardiomyopathy and muscular dystrophy. Lmna null mice develop these disorders and have a lifespan of 7–8 weeks. Emd null mice show no overt pathology and have normal skeletal muscle but with regeneration defects. We generated mice with germline deletions of both Lmna and Emd to determine the effects of combined loss of the encoded proteins. Mice without lamin A/C and emerin are born at the expected Mendelian ratio, are grossly normal at birth but have shorter lifespans than those lacking only lamin A/C. However, there are no major differences between these mice with regards to left ventricular function, heart ultrastructure or electrocardiographic parameters except for slower heart rates in the mice lacking both lamin A/C and emerin. Skeletal muscle is similarly affected in both of these mice. Lmna+/− mice also lacking emerin live to at least 1 year and have no significant differences in growth, heart or skeletal muscle compared to Lmna+/− mice. Deletion of the mouse gene encoding lamina-associated protein 1 leads to prenatal death; however, mice with heterozygous deletion of this gene lacking both lamin A/C and emerin are born at the expected Mendelian ratio but had a shorter lifespan than those only lacking lamin A/C and emerin. These results show that mice with combined deficiencies of three interacting nuclear envelope proteins have normal embryonic development and that early postnatal defects are primarily driven by loss of lamin A/C or lamina-associated polypeptide 1 rather than emerin.

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

“…Proteins were extracted from mouse tissues, separated by electrophoresis in SDS-polyacrylamide slab gels, transferred to nitrocellulose membranes, and analyzed by immunoblotting using methods described previously ( 60 ). Primary antibodies for immunoblotting were rabbit anti-lamin A/C (Santa Cruz) at 1:5,000 dilution, rat monoclonal anti-prelamin A 3C8 ( 61 ) (kindly provided by Loren Fong and Stephen G. Young, University of California, Los Angeles) at 1:3,000 dilution, and mouse anti-GAPDH (Ambion) at 1:3,000 dilution.…”

A Glimpse into Chromatin Organization and Nuclear Lamina Contribution in Neuronal Differentiation

“…The redistribution of chromatin is needed during development to specify the cell type's fate and is essential to cell fitness and function. Alterations in key components of the chromatin 3D reorganization such as the nuclear lamina induce aberrations during development that potentially leads to organism death [42]. Indeed, a homozygous LMNA mutation leads to prenatal lethality in humans, whereas in mice LMNA mutation is not lethal and results in different pathologies a few weeks after birth [42].…”

“…Alterations in key components of the chromatin 3D reorganization such as the nuclear lamina induce aberrations during development that potentially leads to organism death [42]. Indeed, a homozygous LMNA mutation leads to prenatal lethality in humans, whereas in mice LMNA mutation is not lethal and results in different pathologies a few weeks after birth [42]. Intriguingly, upon differentiation, some genes move towards or from the nuclear lamina [43] according to their activation or repression state.…”

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

“…Immunoblotting of proteins isolated from mouse tissues. Proteins were extracted from mouse tissues, separated by electrophoresis in SDS-polyacrylamide slab gels, transferred to nitrocellulose membranes, and analyzed by immunoblotting using methods described previously (55). Primary antibodies for immunoblotting were rabbit anti-lamin A/C (Santa Cruz) at 1:5,000 dilution, rat monoclonal anti-prelamin A 3C8 (56) at 1:3,000 dilution, and mouse anti-GAPDH (Ambion) at 1:3,000 dilution.…”