Developmental Biology Flow-Induced Asymmetry

Nancy R. Gough

Science’s STKE, AAAS, Washington, DC 20005, USA

Mammalian embryos initially develop symmetrically; then, in response to Nodal signaling and the action of the transcription factor Pitx2, organ asymmetry occurs. For example, during embryonic development, two blood vessels on the right side--the right sixth branchial arch artery and the dorsal aorta--undergo complete regression, resulting in the formation of the asymmetrical aortic arch and the pulmonary trunk (see Snider and Conway). Yashiro et al. determined that although Pitx2 activity was required for regression of the sixth branchial arch artery, which is the first vessel to regress, expression of this gene was not required in the artery itself. Instead, Pitx2 was required for a morphological change, the formation of a spiral structure of the myocardial left outflow tract, a structure through which blood leaves the heart. In animals in which the outflow tract did not spiral, regression of neither the right sixth branchial arch artery nor the right dorsal aorta occurred. Echocardiography showed that after the formation of the spiral structure, the blood flow to the right side vessels destined for regression was reduced, whereas blood flow to the left side vessels was greater than before the morphological change. Furthermore, this change in blood flow was lost in embryos with a promoter-mutated Pitx2 (Pitx^ASE/ASE), which also lacked a spiral form to the outflow tract and had persistent right vessels. To confirm that decreased blood flow was the signal for regression, the authors ligated the left sixth branchial arch artery prior to the formation of the spiral structure by the outflow tract and found that the left-side vessels (sixth branchial arch artery and dorsal aorta) regressed and the right, unligated vessels persisted. In the persistent left vessels in wild-type animals, there was increased expression of the gene encoding platelet-derived growth factor-A (PDGF-A) and increased phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) compared with that in the right vessels after the morphological change. Again, this difference was lost in the Pitx^ASE/ASE embryos. Simultaneous pharmacological inhibition of PDGFR and VEGFR triggered bilateral loss of the sixth branchial arch arteries. Thus, the authors suggest that the Nodal-Pitx2 pathway triggers a morphological change that increases blood flow on the left side and decreases blood flow on the right side, producing an asymmetric signal of growth factor signaling, allowing the side with the higher blood flow to survive and the side with less to regress.

P. Snider, S. J. Conway, The power of blood. Nature 450, 180-181 (2007). [PubMed]

K. Yashiro, H. Shiratori, H. Hamada, Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 450, 285-288 (2007). [PubMed]