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Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10615-E10624. doi: 10.1073/pnas.1811624115. Epub 2018 Oct 23.

Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development.

Steimle JD1,2,3, Rankin SA4,5,6,5, Slagle CE7,8,9,10, Bekeny J1,2,3, Rydeen AB1,2,3, Chan SS11,12, Kweon J1,2,3, Yang XH1,2,3, Ikegami K1,2,3, Nadadur RD1,2,3, Rowton M1,2,3, Hoffmann AD1,2,3, Lazarevic S1,2,3, Thomas W13,14, Boyle Anderson EAT15, Horb ME13,14, Luna-Zurita L16,17, Ho RK12, Kyba M11,12, Jensen B18, Zorn AM4,5,6,5, Conlon FL7,8,9,10, Moskowitz IP19,2,3.

Author information

1
Department of Pediatrics, University of Chicago, Chicago, IL 60637.
2
Department of Pathology, University of Chicago, Chicago, IL 60637.
3
Department of Human Genetics, University of Chicago, Chicago, IL 60637.
4
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Research Foundation, Cincinnati, OH 45229.
5
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229.
6
Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229.
7
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
8
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
9
Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
10
The University of North Carolina McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
11
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.
12
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455.
13
National Xenopus Resource, Marine Biological Laboratory, Woods Hole, MA 02543.
14
Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA 02543.
15
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637.
16
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
17
Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes, San Francisco, CA 94158.
18
Amsterdam Cardiovascular Sciences, Department of Medical Biology, Amsterdam University Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
19
Department of Pediatrics, University of Chicago, Chicago, IL 60637; imoskowitz@uchicago.edu.

Abstract

Codevelopment of the lungs and heart underlies key evolutionary innovations in the transition to terrestrial life. Cardiac specializations that support pulmonary circulation, including the atrial septum, are generated by second heart field (SHF) cardiopulmonary progenitors (CPPs). It has been presumed that transcription factors required in the SHF for cardiac septation, e.g., Tbx5, directly drive a cardiac morphogenesis gene-regulatory network. Here, we report instead that TBX5 directly drives Wnt ligands to initiate a bidirectional signaling loop between cardiopulmonary mesoderm and the foregut endoderm for endodermal pulmonary specification and, subsequently, atrial septation. We show that Tbx5 is required for pulmonary specification in mice and amphibians but not for swim bladder development in zebrafish. TBX5 is non-cell-autonomously required for pulmonary endoderm specification by directly driving Wnt2 and Wnt2b expression in cardiopulmonary mesoderm. TBX5 ChIP-sequencing identified cis-regulatory elements at Wnt2 sufficient for endogenous Wnt2 expression domains in vivo and required for Wnt2 expression in precardiac mesoderm in vitro. Tbx5 cooperated with Shh signaling to drive Wnt2b expression for lung morphogenesis. Tbx5 haploinsufficiency in mice, a model of Holt-Oram syndrome, caused a quantitative decrement of mesodermal-to-endodermal Wnt signaling and subsequent endodermal-to-mesodermal Shh signaling required for cardiac morphogenesis. Thus, Tbx5 initiates a mesoderm-endoderm-mesoderm signaling loop in lunged vertebrates that provides a molecular basis for the coevolution of pulmonary and cardiac structures required for terrestrial life.

KEYWORDS:

Hedgehog signaling; TBX5; Wnt signaling; heart development; lung development

PMID:
30352852
PMCID:
PMC6233116
[Available on 2019-05-06]
DOI:
10.1073/pnas.1811624115

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