title: Loss of all 3 Extended Synaptotagmins does not affect normal mouse development, viability or fertility.
abstract: The extended synaptotagmins, E-Syt1, 2 and 3, are multiple C2 domain membrane proteins that are tethered to the endoplasmic reticulum and interact in a calcium dependent manner with plasma membrane phospholipids to form endoplasmic reticulum - plasma membrane junctions. These junctions have been implicated in the exchange of phospholipids between the 2 organelles. The E-Syts have further been implicated in receptor signaling and endocytosis and can interact directly with fibroblast growth factor and other cell surface receptors. Despite these multiple functions, the search for a requirement in vivo has been elusive. Most recently, we found that the genes for E-Syt2 and 3 could be inactivated without effect on mouse development, viability, fertility or morphology. We have now created insertion and deletion mutations in the last of the mouse E-Syt genes. We show that E-Syt1 is specifically expressed throughout the embryonic skeleton during the early stages of chrondrogenesis in a pattern quite distinct from that of E-Syt2 or 3. Despite this, E-Syt1 is also not required for mouse development and propagation. We further show that even the combined inactivation of all 3 E-Syt genes has no effect on mouse viability or fertility in the laboratory. However, this inactivation induces an enhancement in the expression of the genes encoding Orp5/8, Orai1, STIM1 and TMEM110, endoplasmic reticulum - plasma membrane junction proteins that potentially could compensate for E-Syt loss. Given the multiple functions suggested for the E-Syts and their evolutionary conservation, our unexpected findings suggest that they may only provide a survival advantage under specific conditions that have as yet to be identified.
authors.affiliation: a Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Center , Quebec , QC , Canada.|b Department of Molecular Biology , Medical Biochemistry and Pathology, Faculty of Medicine, Laval University , Québec , QC , Canada.
authors.forename: Michel G
authors.initials: MG
authors.lastname: Tremblay
authors.affiliation: a Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Center , Quebec , QC , Canada.|b Department of Molecular Biology , Medical Biochemistry and Pathology, Faculty of Medicine, Laval University , Québec , QC , Canada.
authors.forename: Tom
authors.initials: T
authors.lastname: Moss
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D005298:Fertility; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D008168:Lung / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016254:Mutagenesis, Insertional; D013154:Spleen / Q000378:metabolism; D050857:Synaptotagmins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D050857:Synaptotagmins
keywords: Developmental Expression Profiling; E-Syt1; E-Syt2; E-Syt3; ESyt1; ESyt2; ESyt3; Expression Profiling; Extended-Synaptotagmin; Gene Deletion; Viability' Mouse