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, 18 (3), 480-5

Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFbeta-mediated Outflow Tract Septation

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Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFbeta-mediated Outflow Tract Septation

Peng Li et al. Dev Cell.

Abstract

In many experimental models and clinical examples, defects in the differentiation of the second heart field (SHF) and heart outflow tract septation defects are combined, although the mechanistic basis for this relationship has been unclear. We found that as the initial SHF population incorporates into the outflow tract, it is replenished from the surrounding progenitor territory. In retinoic acid (RA) receptor mutant mice, this latter process fails, and the outflow tract is shortened and misaligned as a result. As an additional consequence, the outflow tract is misspecified along its proximal-distal axis, which results in ectopic expression of TGFbeta2 and ectopic mesenchymal transformation of the endocardium. Reduction of TGFbeta2 gene dosage in the RA receptor-deficient background restores septation but does not rescue alignment defects, indicating that excess TGFbeta causes septation defects. This may be a common pathogenic pathway when second heart field and septation defects are coupled.

Figures

Fig. 1
Fig. 1
Visualization of endogenous RA response. A–C. Xgal stained sections of normal RARE-lacZ transgenic embryos are shown at E8.75, E9.5, and E10.5 in transverse section. D–E. Sagittal sections of control (D) and RARα1/RARβ mutant (E) littermate embryos at E9.5. Brackets indicate the splanchnic mesoderm (SpM). A, atria; en, endoderm; OFT, outflow tract; V, ventricle; arrowheads, OFT myocardium.
Fig. 2
Fig. 2
Markers of the SHF. Littermate pairs were analyzed for expression of Isl1 (E10.5; A,B), Nkx2.5Cre/R26R (E9.75; C,D), GATA4 (E9.5; E,F), and Mef2cCre/R26R (G–R). Asterisks, caudal portion of the SHF. Related images are in Fig. S2.
Fig. 3
Fig. 3
OFT axial misspecification and elevated TGFβ cause CAT. A–B. Ectopic expression of the proximal marker MLC2v in the distal OFT of RAR mutant embryos at E10.5. C–D. Endocardial mesenchyme (arrowheads) in the distal OFT of mutant embryos at E10.5, visualized by Tie2Cre/R26R. Gray lines in A–D are positioned at the 90° bend between the proximal and distal segments of the OFT. E–F. Elevated Tgfb2 expression in the distal OFT in mutants at E9.75. G–I. Rescue of septation defects in E14.5 RAR mutants by reduced Tgfb2 gene dosage: a normal control embryo (G), a RARα1/RARβ mutant with CAT (H), and a RARα1/RARβ mutant also heterozygous for Tgfb2 (I). In rescued embryos, OFT septation occurs but both outflow vessels originate from the right ventricle (the RV source of the ascending aorta is not seen in this panel). Ao, ascending aorta; PT, pulmonary trunk. See also Fig. S3.

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