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 Berta, Junliang Pan () and Eugene C. Butcher ()
Additional contact information
Thanh Theresa Dinh: Stanford University School of Medicine
Menglan Xiang: Stanford University School of Medicine
Anusha Rajaraman: Stanford University School of Medicine
Yongzhi Wang: Stanford University School of Medicine
Nicole Salazar: Stanford University School of Medicine
Yu Zhu: Stanford University School of Medicine
Walter Roper: Columbia University Vagelos College of Physicians and Surgeons
Siyeon Rhee: Stanford University
Kevin Brulois: Stanford University School of Medicine
Ed O’Hara: Palo Alto Veterans Institute for Research
Helena Kiefel: Stanford University School of Medicine
Truc M. Dinh: Palo Alto Veterans Institute for Research
Yuhan Bi: Stanford University School of Medicine
Dalila Gonzalez: University of California, San Diego
Evan P. Bao: Palo Alto Veterans Institute for Research
Kristy Red-Horse: Stanford University
Peter Balogh: University of Pécs Medical School
Fanni Gábris: University of Pécs Medical School
Balázs Gaszner: University of Pécs Medical School
Gergely Berta: University of Pécs Medical School
Junliang Pan: Palo Alto Veterans Institute for Research
Eugene C. Butcher: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34991-2

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