title: Extended Synaptotagmin (ESyt) Triple Knock-Out Mice Are Viable and Fertile without Obvious Endoplasmic Reticulum Dysfunction.
abstract: Extended synaptotagmins (ESyts) are endoplasmic reticulum (ER) proteins composed of an N-terminal transmembrane region, a central SMP-domain, and five (ESyt1) or three C-terminal cytoplasmic C2-domains (ESyt2 and ESyt3). ESyts bind phospholipids in a Ca2+-dependent manner via their C2-domains, are localized to ER-plasma membrane contact sites, and may catalyze lipid exchange between the plasma membrane and the ER via their SMP-domains. However, the overall function of ESyts has remained enigmatic. Here, we generated triple constitutive and conditional knock-out mice that lack all three ESyt isoforms; in addition, we produced knock-in mice that express mutant ESyt1 or ESyt2 carrying inactivating substitutions in the Ca2+-binding sites of their C2A-domains. Strikingly, all ESyt mutant mice, even those lacking all ESyts, were apparently normal and survived and bred in a manner indistinguishable from control mice. ESyt mutant mice displayed no major changes in brain morphology or synaptic protein composition, and exhibited no large alterations in stress responses. Thus, in mice ESyts do not perform an essential role in basic cellular functions, suggesting that these highly conserved proteins may perform a specialized role that may manifest only during specific, as yet untested challenges.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA, 94305-5453, United States of America.|Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Stanford, CA, United States of America.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sclip
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA, 94305-5453, United States of America.
authors.forename: Taulant
authors.initials: T
authors.lastname: Bacaj
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA, 94305-5453, United States of America.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Giam
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA, 94305-5453, United States of America.|Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Stanford, CA, United States of America.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005298:Fertility / Q000235:genetics*; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D013312:Stress, Physiological; D050857:Synaptotagmins / Q000172:deficiency* / Q000235:genetics
chemical_list: D050857:Synaptotagmins; D002118:Calcium