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

Thanh Theresa Dinh, Menglan Xiang, Anusha Rajaraman, Yongzhi Wang, Nicole Salazar, Yu Zhu, Walter Roper, Siyeon Rhee, Kevin Brulois, Ed O’Hara, Helena Kiefel, Truc M. Dinh, Yuhan Bi, Dalila Gonzalez, Evan P. Bao, Kristy Red-Horse, Peter Balogh, Fanni Gábris, Balázs Gaszner, Gergely BertaJunliang Pan, Eugene C. Butcher

Research output: Contribution to journalArticlepeer-review

Abstract

Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control 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 of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. The Madcam1 element 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.

Original languageEnglish
Article number7448
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Subject classification (UKÄ)

  • Cell and Molecular Biology

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