RETINOIC ACID RECEPTOR GAMMA ACTIVITY IN ENDOTHELIAL CELLS REGULATES B LYMPHOPOIESIS, ERYTHROPOIESIS, PLATELET PRODUCTION, VASCULATURE STRUCTURE AND ADIPOCYTE SIZE IN A SEX-DEPENDENT MANNER

Abstract

We have previously shown that mice null for the vitamin A receptor, retinoic acid receptor gamma (Rarg-/- mice) developed a myeloproliferative-like syndrome, accompanied by bone marrow (BM) B lymphopenia and reduced BM erythrocytes, and we have shown that all of these phenotypes were microenvironment-induced. Here, we deleted Rarg in tamoxifen-inducible Cdh5(PAC)CreERT2 (VE-Cadherin)-expressing endothelial cells (ECs) in 3-week old mice and investigated their haematopoiesis and BM niche parameters at 12 weeks of age. All mice were crossed to Rosa26mTmG reporter mice which confirmed that Rarg deletion was restricted to the ECs. Male and female EC:Rarg-/-mTmG mice had significant reductions of B lymphocytes in their peripheral blood (PB), accompanied by significant reductions in BM mature recirculating B cells compared to sex-matched EC:Rarg+/+mTmG mice. No significant phenotypes were observed in the maturing B lymphocyte populations in the BM or spleen of female mice, whereas male mice had reduced numbers of pre-pro-B and increased numbers of pre-B lymphocytes in their BM. Female EC:Rarg-/-mTmG mice also developed PB thrombocytopenia and macrocytic anaemia, accompanied by increased numbers of erythrocytes in the spleen. Male EC:Rarg-/-mTmG mice developed thrombocytosis and had significantly reduced numbers of mature BM erythrocytes. The BM sinusoidal vessels in female, but not male, EC:Rarg-/-mTmG mice were significantly dilated, and these female mice had smaller adipocytes in their BM. Collectively, our data show that RARg activity in ECs is essential for mature cell B lymphopoiesis, platelet production and erythropoiesis in male and female mice. Furthermore, RARg activity in ECs is essential for the regulation of sinusoidal vasculature structure and adipocyte production in female mice. The mechanisms underlying these phenotypes are currently under investigation.