Genetic Interaction of Hepatocyte Nuclear Factor 6 and Notch Signaling Within the Liver Charles Vanderpool, MD 1 Erin Sparks 2 , Kari Huppert 2 Stacey Huppert, PhD 2 1 D. Brent Polk Division of Pediatric Gastroenterology, Hepatology, and Nutrition 2 Department of Cell and Developmental Biology and Center for Stem Cell Biology
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Genetic Interaction of HepatocyteNuclear Factor 6 and Notch Signaling
Within the Liver
Charles Vanderpool, MD1
Erin Sparks2, Kari Huppert2
Stacey Huppert, PhD2
1D. Brent Polk Division of Pediatric Gastroenterology, Hepatology, and Nutrition2Department of Cell and Developmental Biology and Center for Stem Cell Biology
Disclosures
I have no financial relationships to disclose within the past 12 months relevant to my
presentation
My presentation does not include discussion of off-label or investigational use of medications
Cholangiopathies and Bile Duct Development
• Pediatric cholestatic liver disease – Biopsy findings and clinical course can differ amongst
patients with similar intrahepatic bile duct (IHBD) defects
– Alagille Syndrome: phenotypic variance despite defined genetic alterations in Notch signaling
• Clinical variance could be caused by alterations in signaling pathways responsible for various steps in ductal development
Hepatocytes
Cholangiocytes
Hepatoblasts
IHBD System
Bile Duct
Portal vein
Specification Morphogenesis Maintenance
Specification Morphogenesis Maintenance
HNF-1β
HNF-6 Loss3
Global HNF6 null
75% mortality
Notch loss1,2
Liver-specific Conditional RBP-jκflox/flox
✖ ✖
Notch and Hepatocyte Nuclear Factor-6
25% survivorsNormal IHBDs
Paucity of IHBDsChronic cholestasis
??? 2,4
HNF-1β
✖ ✖
1Sparks et al. Hepatology 51(2), 20102Zong et al. Development 136, 20093Clotman et al. Development 129, 20024Tanimizu et al. Journal of Cell Science 117, 2004
Questions
• In setting of chronic cholestasis induced by Notch signaling loss
– Does loss of HNF-6 alter the phenotypic severity?
• In the setting of loss of both HNF-6 and Notch signaling