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Liver Development and Zonation

The complex architecture of the mammalian liver begins to establish during embryogenesis and is completed at postnatal stages. Due to its pivotal role in homeostasis, congenital malformations that disrupt liver formation have disastrous consequences for health.  We published that Prox1 is widely expressed in murine bipotent liver progenitors (a.k.a. hepatoblasts) and demonstrated that its activity regulates the delamination of hepatoblasts from the hepatic diverticulum (Sosa-Pineda et al., Nat. Genet. 2000). In a subsequent study, we revealed that Prox1 activity promotes hepatocyte specification and opposes cholangiocyte specification (Seth et al., Development, 2014) in hepatoblasts. These results conclusively established that Prox1 is a crucial regulator of morphogenesis and cell differentiation in the embryonic liver. Determining how Prox1 establishes the fate of hepatocytes and the potential role of specific histone modifiers in this process are ongoing projects in the lab. 

Hepatocytes are exposed to different levels of nutrients and factors along the porto-central axis of the liver lobule; in turn, those cells arrange into metabolic zones that spatially separate distinct functions and allow the organ to respond with precision to nutrient variations. The subdivision of the liver into distinctive metabolic zones is called ‘hepatic zonation’, and in the adult organ is maintained by Wnt/b-catenin signaling. By taking advantage of a novel mouse reporter strain my lab is currently studying how zonation is established in the developing and injured liver, what signals are involved in these processes, and what are the cellular sources that produce those signals.