An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression

Author:

Dinh Thanh Theresa,Xiang MenglanORCID,Rajaraman Anusha,Wang Yongzhi,Salazar Nicole,Zhu Yu,Roper Walter,Rhee SiyeonORCID,Brulois Kevin,O’Hara Ed,Kiefel Helena,Dinh Truc M.,Bi Yuhan,Gonzalez Dalila,Bao Evan P.,Red-Horse KristyORCID,Balogh Peter,Gábris FanniORCID,Gaszner BalázsORCID,Berta Gergely,Pan JunliangORCID,Butcher Eugene C.ORCID

Abstract

AbstractImmunoglobulin family and carbohydrate vascular addressins encoded byMadcam1andSt6gal1control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions ofMadcam1andSt6gal1that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. TheMadcam1element also integrates repressive signals from arterial/capillary Notch effectors. Pan-endothelial COUP-TFII overexpression induces ectopic addressin expression in NKX2-3+capillaries, while NKX2-3 deficiency abrogates expression by HEV. Phylogenetically conserved NCCE are enriched in genes involved in neuron migration and morphogenesis of the heart, kidney, pancreas and other organs. Our results define an NKX-COUP-TFII morphogenetic code that targets expression of mucosal vascular addressins.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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