We are interested in characterizing the cellular and molecular events regulating the formation of the mammalian eyes, in particular the optic vesicles. For these studies, we use mouse models as well as stem cells and iPSCs derived organoids. Using these tools, few years ago we identified that repression of R-spondin2 by the transcription factor Six3 was required for neuroretina cell fate differentiation.
Recent results from RNAseq of developing optic vesicle identified novel genes and pathways that likely responsible for eye formation and we are currently characterizing their functional roles using organoids and mouse models.
Lymphatic Vasculature in Health & Disease
The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. The molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions such as obesity, cardiovascular disease, inflammation, hypertension, atherosclerosis, glaucoma and various neurological disorders such as Alzheimer’s disease (Oliver et al., Cell 2020). We identified the transcription factor Prox1 as the first specific marker of lymphatic endothelial cells, a finding that allowed us to confirm a century-old theory proposing a venous origin of the mammalian lymphatic vasculature (Wigle and Oliver, Cell 1999). We also demonstrated that Prox1 is necessary for lymphatic cell specification (Wigle et al., EMBO J 2002) and that the lymphatic endothelial cell fate is plastic and reprogrammable, and requires constant Prox1 expression (Johnson et al., Genes & Dev 2008). A few years ago, we published the first report of adult onset obesity consequence of lymphatic vasculature defects (Harvey et al., Nature Genetics 2005). We have also been able to characterize the early steps leading to the formation of the mammalian lymphatic vasculature by showing that a Prox1-Vegfr3 autoregulatory feedbackloop is required to regulate the number of LEC progenitors specified and to maintain their identity (Srinivasan et al., Genes & Dev 2014). More recently, we extended those results by identifying that mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance (Ma et al., Science Advances 2021). We have also identified a novel functional role of lymphatics during cardiac growth and repair, as we identified Reelin as a paracrine factor produced by lymphatics and required for normal heart development and cardiac injury response (Liu et al., Nature 2020).