Msx1 杂合性不足改变了 Pax9 缺陷型的心血管表型。

BACKGROUND: Successful 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. RESULTS: In 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. CONCLUSIONS: Msx1 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.

背景：成功的胚胎发生依赖于基因和组织之间的协调相互作用。转录因子 Pax9 和 Msx1 在小鼠颅面形态发生过程中具有遗传相互作用，并且这两种基因缺失的小鼠表现出异常的牙齿和 palate 发育。Pax9 在胚胎中期特异性表达于咽胚层，并且 C57Bl/6 遗传背景下的 Pax9 缺失小鼠也具有影响流出道和主动脉弓动脉的心血管缺陷，导致右心室双出口、颈总动脉缺失和主动脉弓中断。

结果：在这项研究中，我们研究了不同遗传背景和 Msx1 单倍不足对 Pax9 缺陷型心血管表型的影响。与 C57Bl/6 背景下的小鼠相比，同源 CD1-Pax9 小鼠的流出道缺陷发生率显著降低，但主动脉弓缺陷未改变。然而，具有 Msx1 单倍不足的 Pax9 小鼠中断主动脉弓的发生率降低，但更多的情况下，右锁骨下动脉和主动脉弓的颈部分支起源，比 Pax9 小鼠更常见。这种弓状动脉缺陷的改变伴随着第三咽弓神经嵴细胞迁移和第三咽弓动脉平滑肌细胞覆盖的拯救。尽管这种表型的变化理论上可以与产后存活兼容，但使用组织特异性失活 Pax9 来维持正确的 palate 发育，同时诱导心血管缺陷，不能防止突变小鼠的产后死亡。Pax9 小鼠的舌骨和甲状腺软骨形成异常。

结论：Msx1 单倍不足减轻了 Pax9 小鼠的弓状动脉缺陷，可能是通过维持 3 号弓动脉的存活，通过神经嵴细胞向第三咽弓的迁移不受损害。由于 Pax9 小鼠的神经嵴细胞衍生的舌骨和甲状腺软骨也存在缺陷，我们推测咽胚层是一个关键的信号中心，它影响神经嵴细胞的行为，突出了不同组织中的细胞在胚胎发育过程中协同或拮抗作用的能力。