| Proper embryonic development requires precise genetic regulation of cell growth and differentiation. Organogenesis, the origin and formation of internal organs, must be exquisitely choreographed to ensure correct temporal and spatial patterning of functional organs within the developing organism. The liver is a vital organ responsible for hundreds of essential metabolic functions, but the intricate pathways controlling organ specification, differentiation, and positioning have not been fully elucidated. Uncovering the molecular mechanisms involved in hepatogenesis will enhance our understanding of normal liver development as well as inform the design of therapeutics to combat liver disease. Nuclear receptors are evolutionarily recent signal transducers that occupy a special niche in gene regulation, acting as direct connections between a ligand and its downstream transcriptional target. Nuclear receptor signaling governs many physiological processes, however its impact on liver development is not well understood.;In this dissertation, I explore the functions of two nuclear receptor signaling pathways in embryonic zebrafish liver development. First, I define the role of retinoic acid signaling during liver specification. Retinoic acid positively impacts liver development, and individual retinoic acid receptors (RARs) exert distinct effects on hepatic specification. One receptor, Rargb, is uniquely responsible for positioning the liver along the left-right axis and functions upstream of BMP signaling to regulate organ sidedness. Loss of Rargb results in an embryonic phenotype reminiscent of the human heterotaxic condition right atrial isomerism, or Ivemark Syndrome.;Second, I delineate the impact of physiological and environmental estrogens on hepatic differentiation. Estrogenic compounds negatively regulate liver development and exert their effect through estrogen receptor 2 (ESR2) isoforms. In particular, estrogen exposure prevents hepatic differentiation, and embryonic estrogen production and response are carefully orchestrated to enable timely liver maturation. This effect is conserved across vertebrate species.;Together, these studies provide novel insight into the function of nuclear receptor signaling during embryonic liver development. Continued investigation into transcriptional regulation of hepatic specification and differentiation will expand our understanding of and engender new therapies for liver dysfunction. |
