KIT is required for hepatic function during mouse post-natal development |
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Authors: | Laetitia Magnol Marie-Clémence Chevallier Valérie Nalesso Stéphanie Retif Helmut Fuchs Martina Klempt Patricia Pereira Michel Riottot Sandra Andrzejewski Bich-Thuy Doan Jean-Jacques Panthier Anne Puech Jean-Claude Beloeil Martin Hrabe de Angelis Yann Hérault |
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Institution: | 1. Division of Endocrinology, Metabolism and Nutrition, Medical College of Wisconsin, Milwaukee, 53226, WI, USA 5. Qilu Hospital of Shandong University, 44 West Wenhua Road Jinan, 250012, P. R., China 2. Department of Veterans Affairs New Jersey Health Care System, Research Service, East Orange, 07018, NJ, USA 3. Department of Medicine, UMDNJ-New Jersey Medical School, Newark, 07103-2714, NJ, USA 4. Department of Veterans Affairs, Clement J. Zablocki Medical Center, Milwaukee, WI, 53295, USA
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Abstract: | Background Targeted disruption of the murine 3β-hydroxysterol-Δ7-reductase gene (Dhcr7), an animal model of Smith-Lemli-Opitz syndrome, leads to loss of cholesterol synthesis and neonatal death that can be partially rescued by transgenic replacement of DHCR7 expression in brain during embryogenesis. To gain further insight into the role of non-brain tissue cholesterol deficiency in the pathophysiology, we tested whether the lethal phenotype could be abrogated by selective transgenic complementation with DHCR7 expression in the liver. Results We generated mice that carried a liver-specific human DHCR7 transgene whose expression was driven by the human apolipoprotein E (ApoE) promoter and its associated liver-specific enhancer. These mice were then crossed with Dhcr7+/- mutants to generate Dhcr7-/- mice bearing a human DHCR7 transgene. Robust hepatic transgene expression resulted in significant improvement of cholesterol homeostasis with cholesterol concentrations increasing to 80~90 % of normal levels in liver and lung. Significantly, cholesterol deficiency in brain was not altered. Although late gestational lung sacculation defect reported previously was significantly improved, there was no parallel increase in postnatal survival in the transgenic mutant mice. Conclusion The reconstitution of DHCR7 function selectively in liver induced a significant improvement of cholesterol homeostasis in non-brain tissues, but failed to rescue the neonatal lethality of Dhcr7 null mice. These results provided further evidence that CNS defects caused by Dhcr7 null likely play a major role in the lethal pathogenesis of Dhcr7 -/- mice, with the peripheral organs contributing the morbidity. |
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