Abstract
BackgroundSuccessful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch.ResultsIn this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9–/– mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9–/– mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9–/– mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9–/– mice.ConclusionsMsx1 haploinsufficiency mitigates the arch artery defects in Pax9–/– mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9–/– mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.
Highlights
Successful embryogenesis relies on the coordinated interaction between genes and tissues
To investigate if the fully penetrant cardiovascular defects seen in mice on a congenic C57Bl/6 genetic background (B6-Pax9) were recapitulated on a different genetic background we examined Pax9-deficient mice which had been backcrossed in excess of 20 generations on an outbred CD1 genetic background (CD1-Pax9)
CD1-Pax9–/– mice had a significantly lower incidence of double outlet right ventricle (DORV) compared to our published data for B6-Pax9–/– neonates and embryos [3] (n = 24; 16% vs. 79%, p < 0.001; Fig. 2E; Table 1), a very similar incidence of VSD and arch artery defects (IAA and aberrant right subclavian artery (A-RSA)) was observed (Figs. 1I–Q; 2F, G; Table 1)
Summary
Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax and Msx genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax is expressed in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax on a C57Bl/6 genetic background have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Pax is expressed in the pharyngeal endoderm at mid-embryogenesis with wider expression in the craniofacial region and skeletal precursors later in development [6, 7]. Mice lacking Pax die in the neonatal period with cleft palate, tooth agenesis [4] and cardiovascular defects which are the most likely cause of death [2, 3]. Mouse mutants with complete cleft palate die within 24 h of birth without having fed, most likely due to a combination of factors such as the inability to suckle and respiratory distress [10]
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