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Cell Cycle
2014 Jan 01;1316:2616-25. doi: 10.4161/15384101.2014.943573.
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Loss of Extended Synaptotagmins ESyt2 and ESyt3 does not affect mouse development or viability, but in vitro cell migration and survival under stress are affected.
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The Extended Synaptotagmins (Esyts) are a family of multi-C2 domain membrane proteins with orthologs in organisms from yeast to human. Three Esyt genes exist in mouse and human and these have most recently been implicated in the formation of junctions between endoplasmic reticulum and plasma membrane, as well as the Ca(2+) dependent replenishment of membrane phospholipids. The data are consistent with a function in extracellular signal transduction and cell adhesion, and indeed Esyt2 was previously implicated in both these functions in Xenopus. Despite this, little is known of the function of the Esyts in vivo. We have generated mouse lines carrying homozygous deletions in one or both of the genes encoding the highly homologous Esyt2 and Esyt3 proteins. Surprisingly, esyt2(-/-)/esyt3(-/-) mice develop normally and are both viable and fertile. In contrast, esyt2(-/-)/esyt3(-/-) mouse embryonic fibroblasts display a reduced ability to migrate in standard in vitro assays, and are less resistant to stringent culture conditions and to oxidative stress than equivalent wild type fibroblasts.
Figure 2. Expression of Esyt1, â2 and â3 mRNA in adult mouse tissues and MEFs. RT-PCR analyzes are shown for tissues from both wild type esyt2+/+/esyt3+/+ and esyt2â/âesyt3â/â mice as compared with GAPDH.
Figure 3. Expression pattern of the esyt2 and â3 genes in early mouse embryos. Expression was determined by conversion of X-Gal (blue-green) by Ã-galactosidase produced from the gene inserted into the esyt2 and esyt3 gene loci. Enlarged panels on the right show a limb-bud and the hindbrain region of esyt3+/ÃâGal embryos. âaerâ apical ectodermal ridge, âmhbâ midbrain-hindbrain boundary, âfbâ forelimb bud, âhbâ hindlimb bud, âurlâ and âlrlâ upper and lower rhombomere lips, âr2-6â rhombomeres, âovâ otic vesicle, ântâ neural tube, âdrgâ dorsal root ganglion.
Figure 4. Representative Hematoxylin-Eosin staining of sections obtained from 2 11 month old esyt2â/âesyt3â/â sibling males and 2 11 month old esyt2+/+esyt3+/+ sibling males. Organs displayed were those that showed a strong or differential expression of ESyt1, 2 and 3, see Figure 2. (A) The renal cortex of WT and DKO mice are essentially indistinguishable. Renal tubules (RT) and renal corpuscles (RC) with glomeruli (G) and Bowman's space (BS) are indicated. Scale bars 100 μm. (B) Top panels: Lung sections with pleura (P), bronchioles (B) and alveoli (A) indicated, scale bars 200 μm. Bottom: higher magnification of alveoli, scale bars 100âμm. (C) Testis morphology also appears normal, seminiferous tubules (T) and the surrounding Leydig cells (L) are indicated, scale bars 100 μm. (D) White pulp (WP- encircled) with central arteries (CA) and red pulp (RP) of spleen samples are indicated, scale bars 100 μm.
Figure 5. Response of ERK and AKT to extracellular stimulation in esyt2−/− MEFs. Esyt2+/+ and esyt2−/− MEFs were treated at 0 min. with FGF, EGF and FBS and activation of ERK and AKT followed at the indicated times using phospho-specific antibodies (pERK (−1 and −2) and pAKT). ERK2 was detected using a specific antibody and was used as loading control.
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