A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis
Chaoshe Guo, … , Anne Moon, Xue Li
Chaoshe Guo, … , Anne Moon, Xue Li
Published March 1, 2011
Citation Information: J Clin Invest. 2011;121(4):1585-1595. https://doi.org/10.1172/JCI44630.
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Research Article Cardiology

A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis

Abstract

Shared molecular programs govern the formation of heart and head during mammalian embryogenesis. Development of both structures is disrupted in human chromosomal microdeletion of 22q11.2 (del22q11), which causes DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). Here, we have identified a genetic pathway involving the Six1/Eya1 transcription complex that regulates cardiovascular and craniofacial development. We demonstrate that murine mutation of both Six1 and Eya1 recapitulated most features of human del22q11 syndromes, including craniofacial, cardiac outflow tract, and aortic arch malformations. The mutant phenotypes were attributable in part to a reduction of fibroblast growth factor 8 (Fgf8), which was shown to be a direct downstream effector of Six1 and Eya1. Furthermore, we showed that Six1 and Eya1 genetically interacted with Fgf8 and the critical del22q11 gene T-box transcription factor 1 (Tbx1) in mice. Together, these findings reveal a Tbx1-Six1/Eya1-Fgf8 genetic pathway that is crucial for mammalian cardiocraniofacial morphogenesis and provide insights into the pathogenesis of human del22q11 syndromes.

Authors

Chaoshe Guo, Ye Sun, Bin Zhou, Rosalyn M. Adam, XiaoKun Li, William T. Pu, Bernice E. Morrow, Anne Moon, Xue Li

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Figure 1

Six1–/–Eya1–/– mutants phenocopy features of human del22q11 syndromes.

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Six1–/–Eya1–/– mutants phenocopy features of human del22q11 syndromes. ...
(A–F) Gross morphological defects of the OFT and great arteries of newborn mutants (B–F) versus WT control (A). (G–J) H&E histological staining of sectioned hearts revealed VSD and dysmorphology of the outflow valves in a Six1–/–Eya1–/– mutant (I and J) compared with Six1+/–Eya1+/– control (G and H). Ao, aortic artery; BCA, brachiocephalic artery; dA, descending aorta; DLCC, duplicated left common carotid artery; LCC, left common carotid artery; LSC, left subclavian artery; p, pulmonary artery; RCC, right common carotid artery; RRSA, retroesophageal right subclavian artery; RSC, right subclavian artery; V, ventricle; VR, vascular ring. Asterisks denote interrupted aortic arches. Original magnification, ×50 (G and I); ×80 (H and J).