Flt4, also known as VEGFR3 (vascular endothelial growth factor receptor 3), is a receptor tyrosine kinase. It plays crucial roles in lymphangiogenesis and angiogenesis, being essential for the development of the lymphovascular and cardiovascular systems. It is involved in pathways related to cell-cycle regulation, autophagy, inflammasome activation, and glycolytic reprogramming [1,2,4].

In macrophages, upon S. typhimurium infection, Flt4 and its ligand VEGFC are inducibly expressed. Flt4 signaling inhibits CASP1-dependent inflammasome activation and pyroptosis but enhances MAP1LC3/LC3 activation for bacterial elimination. Flt4 mutants lacking the extracellular ligand-binding domain show abnormal production of pro-inflammatory and antimicrobial metabolites [1].

In zebrafish, depletion of flt4 causes cardiac phenotypes such as reduced heart size and altered heart looping, which can be rescued by coinjection of wild-type human Flt4 mRNA but not completely or at all by mRNA harbouring Flt4 TOF variants. This indicates Flt4's role in cardiogenesis [2].

In mice, knocking out the Flt4 gene (FLT4+/- mice) makes them susceptible to high-fat diet-induced obesity, with visceral fat accumulation, abnormal lymphatic vessel morphology, and increased macrophage infiltration and inflammation [3].

In conclusion, Flt4 is essential for the normal development of the cardiovascular and lymphovascular systems, and its function is also implicated in processes like bacterial elimination, obesity development, and potentially in the pathogenesis of congenital heart diseases and Milroy disease as shown through gene-knockout models in mice and zebrafish [1,2,3]. These models have provided valuable insights into the role of Flt4 in specific biological processes and disease conditions.