The Role of Macrophages in Hepatobiliary Development

Project Summary - The role of macrophages in hepatobiliary development The liver is a vital metabolic organ, involved in nutrient metabolism and detoxification of endogenous and exogenous products. To manage exposure to antigens and microbes, the liver harbors ~80% of the body’s residential macrophages. The role of macrophages in liver development is completely unknown. In our preliminary work we demonstrate that genetic or induced loss of macrophages severely affects hepatobiliary development, reducing biliary tree branching and affecting hepatocyte polarization. The objective in our proposed work is to employ macrophage-deficient zebrafish and transgenic reporter strains combined with high-resolution confocal imaging and novel image analysis methods to determine the importance of macrophages for liver development. Our central hypothesis is that macrophages are attracted to the developing liver bud by a temporal and location-specific expression of TNFα, and that macrophages mediate their effect on hepatobiliary development through modulation of TGFβ signaling. Two Specific Aims are proposed to define the role of macrophages for normal hepatobiliary development development. In Specific Aim 1 we will identify the exact periods during development when macrophages interact with the liver, and how their loss affects normal development and function. Specific Aim2 will define the molecular signals by which macrophages are attracted to the developing liver, and how macrophage-derived TGFβ signaling affects liver development. Our proposed work will provide critical new mechanistic insight into the contribution of macrophages to normal hepatobiliary development, and further elucidate the pathogenesis of developmental biliary defects in childhood.