The muscle dystrophy-causing ?K32 lamin A/C mutant does not impair the functions of the nucleoplasmic lamin-A/C-LAP2? complex in mice.

ABSTRACT: A-type lamins are components of the nuclear lamina, a filamentous network of the nuclear envelope in metazoans that supports nuclear architecture. In addition, lamin A/C can also be found in the interior of the nucleus. This nucleoplasmic lamin pool is soluble in physiological buffer, depends on the presence of the lamin-binding protein, lamina-associated polypeptide 2? (LAP2?) and regulates cell cycle progression in tissue progenitor cells. ?K32 mutations in A-type lamins cause severe congenital muscle disease in humans and a muscle maturation defect in Lmna(?K32/?K32) knock-in mice. Mutant ?K32 lamin A/C protein levels were reduced and all mutant lamin A/C was soluble and mislocalized to the nucleoplasm. To test the role of LAP2? in nucleoplasmic ?K32 lamin A/C regulation and functions, we deleted LAP2? in Lmna(?K32/?K32) knock-in mice. In double mutant mice the Lmna(?K32/?K32)-linked muscle defect was unaffected. LAP2? interacted with mutant lamin A/C, but unlike wild-type lamin A/C, the intranuclear localization of ?K32 lamin A/C was not affected by loss of LAP2?. In contrast, loss of LAP2? in Lmna(?K32/?K32) mice impaired the regulation of tissue progenitor cells as in lamin A/C wild-type animals. These data indicate that a LAP2?-independent assembly defect of ?K32 lamin A/C is the predominant cause of the mouse pathology, whereas the LAP2?-linked functions of nucleoplasmic lamin A/C in the regulation of tissue progenitor cells are not affected in Lmna(?K32/?K32) mice.

SUBMITTER: Pilat U 

PROVIDER: S-EPMC4333763 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature