Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants.
Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants.
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DOI：
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发表时间：
1999-11
期刊：
影响因子：
4.6
通讯作者：
J. Barrow;M. Capecchi
中科院分区：
文献类型：
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作者：
J. Barrow;M. Capecchi
菱脑神经嵴在颅面发育中起着多种作用。它们产生颅感觉神经节和大部分颅面骨骼，并且对于颅面肌肉的图案至关重要。Hoxa 1或Hoxa 2功能的丧失会影响多个神经嵴衍生结构的发育。为了了解这两个基因如何在颅面发育中共同发挥作用，产生了一个等位基因，破坏了这两个连锁基因。在双突变体中观察到的一些颅面缺陷是存在于每个单突变体中的那些缺陷的加性组合，这表明每个基因在这些结构的形成中独立地起作用。其他缺陷仅在显示重叠或协同功能的双突变体中发现。我们还发现了Hoxa 2突变体的外在舌和舌骨肌的附着和轨迹的多个缺陷。有趣的是，这些肌肉中的两个，茎突舌肌和茎突舌骨肌的异常轨迹，阻止了舌骨舌肌与舌骨大角的附着，这反过来又与Hoxa 2突变体中腭裂的存在完全相关。我们认为，舌骨舌肌，其功能是压低舌头的侧边缘，当不能使其适当的附件舌骨大角，迫使舌头采取一个异常的姿势，阻止腭架关闭。出乎意料的是，在Hoxa 1/Hoxa 2双突变体中，腭裂的发生率显著降低。我们发现，两个补偿性缺陷，与Hoxa 1功能的丧失，恢复正常附着的舌骨舌肌大角，从而使腭架解除和融合以上扁平的舌头。
The rhombencephalic neural crest play several roles in craniofacial development. They give rise to the cranial sensory ganglia and much of the craniofacial skeleton, and are vital for patterning of the craniofacial muscles. The loss of Hoxa1 or Hoxa2 function affects the development of multiple neural crest-derived structures. To understand how these two genes function together in craniofacial development, an allele was generated that disrupts both of these linked genes. Some of the craniofacial defects observed in the double mutants were additive combinations of those that exist in each of the single mutants, indicating that each gene functions independently in the formation of these structures. Other defects were found only in the double mutants demonstrating overlapping or synergistic functions. We also uncovered multiple defects in the attachments and trajectories of the extrinsic tongue and hyoid muscles in Hoxa2 mutants. Interestingly, the abnormal trajectory of two of these muscles, the styloglossus and the stylohyoideus, blocked the attachment of the hyoglossus to the greater horn of the hyoid, which in turn correlated exactly with the presence of cleft palate in Hoxa2 mutants. We suggest that the hyoglossus, whose function is to depress the lateral edges of the tongue, when unable to make its proper attachment to the greater horn of the hyoid, forces the tongue to adopt an abnormal posture which blocks closure of the palatal shelves. Unexpectedly, in Hoxa1/Hoxa2 double mutants, the penetrance of cleft palate is dramatically reduced. We show that two compensatory defects, associated with the loss of Hoxa1 function, restore normal attachment of the hyoglossus to the greater horn thereby allowing the palatal shelves to lift and fuse above the flattened tongue.