title: Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases.
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.
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037, United States of America.
authors: Olga
authors: O
authors: Tapia
authors: Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States of America.
authors: Loren G
authors: LG
authors: Fong
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037, United States of America.
authors: Michael D
authors: MD
authors: Huber
authors: Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States of America; Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, United States of America.
authors: Stephen G
authors: SG
authors: Young
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037, United States of America.
authors: Larry
authors: L
authors: Gerace
mesh_terms: D000818:Animals; D047108:Embryonic Development; D055786:Gene Knockout Techniques; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000603518:Lem2 protein, mouse; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases