Understanding the roles of Fox transcription factors in blood and lymphatic vessels.
Northwestern University School of Medicine
Professor Tsutomu Kume
Foxc1 and Foxc2 transcription factors have been implicated in the formation of blood and lymphatic vessels. However, the precise functions of Foxc1 and Foxc2 in the vascular system have yet to be fully elucidated.
We recently generated endothelial cell (EC)-specific Foxc mutant mice containing tamoxifen inducible VE-Cadherin-CreERT2 recombinase, which is active in both blood and lymphatic ECs, and Foxc1fl/fl, Foxc2fl/fl or compound Foxc1fl/fl; Foxc2fl/fl alleles. Early postnatal excision of Foxc1 by administration of tamoxifen from P1-P5 impaired mesenteric lymphatic valve maintenance and maturation, whereas excision of Foxc2 significantly reduced the total number of lymphatic valves by ~35% due to regression. Of great interest, combined deletion of Foxc1 and Foxc2 resulted in nearly complete regression of lymphatic valves in the mesentery. Continuing studies are investigating regulation of RHO/ROCK signaling by Foxc1 and Foxc2 during lymphatic valve development and maintenance.
Analysis of the EC-Foxc mutant mouse lines described above also revealed that Foxc1 and Foxc2 are required for blood vessel growth during postnatal retinal angiogenesis. RNA-seq analysis using retinal ECs isolated from EC-Foxc1 and compound EC-Foxc1; EC-Foxc2 mutant mice identified new molecular pathways downstream of Foxc1 and Foxc2.