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 5

Fgf8 rescues EMT defects in Six1/Eya1 mutant OFT explants.

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Fgf8 rescues EMT defects in Six1/Eya1 mutant OFT explants. (A–H) Six...
(A–H) Six1–/–Eya1–/– mutants (E–H) had hypoplastic OFT cushions compared with WT littermate controls (A–D). Shown are serial histological sections of E11.5 outflow vessels proceeding from proximal (A and E) to distal (D and H). Brackets in A–D indicate WT OFT cushions, which were hypoplastic in the mutants (asterisks). Myo, myocardium. (I–K) The compound mutants (J and K) had fewer endothelial cells migrating from the OFT explant, undergoing EMT, and invading the gel than did WT controls (I) in cultured E9.5 OFTs. (L–N) The EMT defect was rescued by rFgf8b in the explant culture. Original magnification, ×230 (A–H); ×100 (I–N). (O and P) Quantification of results in I–N. White bars, without rFgf8b; gray bars, with rFgf8b. Student’s t test. n = 6 (control); 3 (Six1+/–Eya1–/– and Six1–/–Eya1–/–).