Lamina-Associated Polypeptide 2α Loss Impairs Heart Function and Stress Response in Mice

Abstract

Rationale: Lamina-associated polypeptide (LAP)2␣ is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2␣ lead to cardiac disorders in humans, we hypothesized that these factors may play important roles in heart development and adult tissue homeostasis. Objective: We asked whether the presence of LAP2␣ was required for normal cardiac function. Methods and Results: To study the molecular mechanisms of the disease, we analyzed heart structure and function in complete and conditional Lap2␣ ؊/؊ mice as well as Lap2␣ ؊/؊ /Mdx mutants. Unlike conditional deletion of LAP2␣ in late embryonic striated muscle, its complete knockout caused systolic dysfunction in young mice, accompanied by sporadic fibrosis in old animals, as well as deregulation of major cardiac transcription factors GATA4 and myocyte enhancer factor 2c. Activation of compensatory pathways, including downregulation of ␤-adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic ␤-adrenergic stimulation and stalled the progression of LAP2␣-deficient hearts from hypertrophy toward cardiac failure. Key Words: lamins Ⅲ LAP2␣ Ⅲ dilated cardiomyopathy Ⅲ ␤-adrenergic receptors D ilated cardiomyopathy (DCM) is a primary myocardial disease characterized by dilation and impaired contraction of one or both heart ventricles. One of the genes most frequently involved in the development of DCM is LMNA, which encodes the nuclear intermediate filament proteins lamin A and lamin C 1 . Mutations in lamin A/C cause the most severe forms of DCM, posing a high risk of heart failure in symptomatic patients. 1 Besides heart muscle disease, mutations in LMNA cause a variety of pathological conditions in skeletal muscle, skin, nerve, bone, and adipose tissue, known as laminopathies, 2 emphasizing the importance of the search for molecular disease mechanisms. Dystrophin deficiency in anRecently, research on laminopathies has focused on lamin A/C-interacting proteins, whose mutations have been linked to a similar spectrum of human disorders. 3 One of the best studied lamin A/C-binding partners is lamina associated polypeptide (LAP)2␣, an unusual splice variant of the mammalian LAP2 gene. 4 All LAP2 proteins (␣, ␤, ␥, ␦, , ) share a common chromatin-binding structural motif called the LEM (LAP2-emerin-MAN1) domain at their N terminus. The C terminus of most LAP2 variants comprises a transmembrane region, which targets them to the inner nuclear membrane, where they serve mainly structural roles. 5 LAP2␣ lacks the common LAP2 transmembrane domain and possesses an additional chromatin-binding region at its C-terminal end, which mediates targeting to the nuclear interior. 4 In the nucleoplasm LAP2␣ specifically interacts with a fraction of lamin A/C via its unique C-terminal tail. 6 Together, LAP2␣ and lamin A/C influence various nuclear processes, such as epigenetic chromatin regulation, gene expression, and signal transduction. 7 In particular, LAP2␣-l...

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

“…TMPO encodes multiple transmembrane and nucleoplasmic isoforms of lamina-associated polypeptide (LAP) 2. This report is consistent with the finding that depletion of the nucleoplasmic alpha isoform of LAP2 causes cardiac dysfunction in mice [48]. Mutations and polymorphisms in SYNE1 and SYNE2 genes, which respectively encode the KASH domain proteins nesprin-1 and nesprin-2, have also been reported in patients with muscular dystrophy and cardiomyopathy; disruption of the orthologous genes in mice causes skeletal and cardiac myopathy [49][50][51][52].…”

A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha

“…Deletion of exon 4 of the Tmpo gene generated mice specifically lacking LAP2alpha and leads to the selective loss of nucleoplasmic lamin A/C (Naetar et al 2008). Loss of LAP2alpha causes tissue-specific phenotypes, including increased proliferation of tissue progenitor cells in epidermis, colon, and the hematopoietic system (Naetar et al 2008), delayed skeletal muscle differentiation (Gotic et al 2010b), and impaired heart function (Gotic et al 2010a). However, the molecular mechanisms remain elusive.…”

Circulation Research Thematic Synopsis

“…Lamina-Associated Polypeptide 2␣ Loss Impairs Heart Function and Stress Response in Mice; Gotic et al 61 …”