Abstract
The nuclear lamina, along with associated nuclear membrane proteins, is a nexus for regulating signaling in the nucleus. Numerous human diseases arise from mutations in lamina proteins, and experimental models for these disorders have revealed aberrant regulation of various signaling pathways. Previously, we reported that the inner nuclear membrane protein Lem2, which is expressed at high levels in muscle, promotes the differentiation of cultured myoblasts by attenuating ERK signaling. Here, we have analyzed mice harboring a disrupted allele for the Lem2 gene (Lemd2). No gross phenotypic defects were seen in heterozygotes, although muscle regeneration induced by cardiotoxin was delayed. By contrast, homozygous Lemd2 knockout mice died by E11.5. Although many normal morphogenetic hallmarks were observed in E10.5 knockout embryos, most tissues were substantially reduced in size. This was accompanied by activation of multiple MAP kinases (ERK1/2, JNK, p38) and AKT. Knockdown of Lem2 expression in C2C12 myoblasts also led to activation of MAP kinases and AKT. These findings indicate that Lemd2 plays an essential role in mouse embryonic development and that it is involved in regulating several signaling pathways. Since increased MAP kinase and AKT/mTORC signaling is found in other animal models for diseases linked to nuclear lamina proteins, LEMD2 should be considered to be another candidate gene for human disease.
Highlights
The nuclear envelope (NE) is a specialized domain of the ER that contains inner (INM) and outer (ONM) nuclear membranes joined at nuclear pore complexes and lined by the nuclear lamina
Some of these transmembrane proteins have been characterized in detail, including the lamin B receptor (LBR), emerin, Lamina-Associated Polypeptide 1 (LAP1), LAP2, and MAN1 [7,10]
The gene trap introduced a sequence between exons 3 and 4 of Lemd2 that contains a splice acceptor site (SA), a cDNA encoding the β-galactosidase reporter linked to neomycin, and a SV40 cleavage/polyadenylation site (Fig. 1A)
Summary
The nuclear envelope (NE) is a specialized domain of the ER that contains inner (INM) and outer (ONM) nuclear membranes joined at nuclear pore complexes and lined by the nuclear lamina (reviewed in [1,2,3]). The ONM is continuous with more peripheral ER, many transmembrane proteins are highly concentrated at the INM, partly due to their interactions with lamins and/or chromatin (reviewed in [9]) Some of these transmembrane proteins have been characterized in detail, including the lamin B receptor (LBR), emerin, Lamina-Associated Polypeptide 1 (LAP1), LAP2, and MAN1 [7,10]. The nuclear lamina is involved in organizing the structure of the NE, attaching chromatin to the INM, modulating interphase chromosome structure, and anchoring the cytoplasmic cytoskeleton to the nucleus [3,10] These functions involve the polymeric nuclear lamin core as well as integral and peripheral membrane proteins associated with nuclear membranes
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