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; Eugene C Butcher

doi:10.1038/s41467-022-34991-2

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

Nat Commun. 2022 Dec 2;13(1):7448. doi: 10.1038/s41467-022-34991-2.

Authors

Thanh Theresa Dinh^#^{1

2}, Menglan Xiang^#^{1

2}, Anusha Rajaraman^#^{1

2

3}, Yongzhi Wang^{1

4}, Nicole Salazar¹, Yu Zhu¹, Walter Roper⁵, Siyeon Rhee⁶, Kevin Brulois^{1

2}, Ed O'Hara², Helena Kiefel¹, Truc M Dinh², Yuhan Bi^{1

2}, Dalila Gonzalez⁷, Evan P Bao², Kristy Red-Horse^{6

8

9}, Peter Balogh^{10

11}, Fanni Gábris^{10

11}, Balázs Gaszner¹², Gergely Berta¹³, Junliang Pan^{14

15}, Eugene C Butcher^{16

17

18}

Affiliations

¹ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
³ Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
⁴ Department of Clinical Science Malmo, Section of Surgery, Lund University, Malmo, Sweden.
⁵ Columbia University Vagelos College of Physicians and Surgeons, New York City, NY, USA.
⁶ Department of Biology, Stanford University, Stanford, CA, USA.
⁷ University of California, San Diego, La Jolla, CA, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Howard Hughes Medical Institute, Stanford, CA, USA.
¹⁰ Department of Immunology and Biotechnology, University of Pécs Medical School, Pécs, Hungary.
¹¹ Lymphoid Organogenesis Research Team, Szentágothai Research Center, Pécs, Hungary.
¹² Department of Anatomy, University of Pécs Medical School, Pécs, Hungary.
¹³ Department of Medical Biology and Central Electron Microscopy Laboratory, University of Pécs Medical School, Pécs, Hungary.
¹⁴ Palo Alto Veterans Institute for Research, Palo Alto, CA, USA. jpan@stanford.edu.
¹⁵ The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. jpan@stanford.edu.
¹⁶ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ebutcher@stanford.edu.
¹⁷ Palo Alto Veterans Institute for Research, Palo Alto, CA, USA. ebutcher@stanford.edu.
¹⁸ The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. ebutcher@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Arteries
Cell Movement
Endothelial Cells*
Morphogenesis / genetics
Veins*

Abstract

Publication types

MeSH terms

Grants and funding