Abstract
Disabled-1 (Dab1) protein is an intracellular adaptor of reelin signaling required for prenatal neuronal migration, as well as postnatal neurotransmission, memory formation and synaptic plasticity. Yotari, an autosomal recessive mutant of the mouse Dab1 gene is recognizable by its premature death, unstable gait and tremor. Previous findings are mostly based on neuronal abnormalities caused by Dab1 deficiency, but the role of the reelin signaling pathway in nonneuronal tissues and organs has not been studied until recently. Hepatocytes, the most abundant cells in the liver, communicate via gap junctions (GJ) are composed of connexins. Cell communication disruption in yotari mice was examined by analyzing the expression of connexins (Cxs): Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 during liver development at 13.5 and 15.5 gestation days (E13.5 and E15.5). Analyses were performed using immunohistochemistry and fluorescent microscopy, followed by quantification of area percentage covered by positive signal. Data are expressed as a mean ± SD and analyzed by one-way ANOVA. All Cxs examined displayed a significant decrease in yotari compared to wild type (wt) individuals at E13.5. Looking at E15.5 we have similar results with exception of Cx37 showing negligible expression in wt. Channels formation triggered by pathological stimuli, as well as propensity to apoptosis, was studied by measuring the expression of Pannexin1 (Panx1) and Apoptosis-inducing factor (AIF) through developmental stages mentioned above. An increase in Panx1 expression of E15.5 yotari mice, as well as a strong jump of AIF in both phases suggesting that yotari mice are more prone to apoptosis. Our results emphasize the importance of gap junction intercellular communication (GJIC) during liver development and their possible involvement in liver pathology and diagnostics where they can serve as potential biomarkers and drug targets.
Highlights
The liver is one of the first organs where the connexin proteins (Cxs) were described [1]
Cell to cell communication disruption was examined by measuring immunoexpression of connexins (Cx26, Cx32, Cx37, Cx40, Cx43, Cx45) on mouse embryonic livers at a different stage of development (E13.5 and E15.5)
Knowing that liver connexin expression was altered upon liver organogenesis as well as in disease, we wanted to examine does Reelin signaling pathway has some influence on mentioned using yotari (Dab1-/-) mice as a model organism
Summary
The liver is one of the first organs where the connexin proteins (Cxs) were described [1]. Apart from connexins, which can form hemichannels and gap junctions, pannexins (Panxs) form only channels [5,6,7] taking part in cell inflammation and death processes [8,9,10]. It is a three-member family of proteins (Panx, Panx, Panx3) [11] similar to connexins by structure and permeability [7]. Cx26 and Cx43 were found in sinusoidal endothelial cells [13] and of all three pannexins, Panx was found in the mouse hepatocytes as a contributor of the inflammasome, a caspase-1-activating multiprotein complex [21]
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