Neural Crest-Specific Loss of Prkar1a Causes Perinatal Lethality Resulting from Defects in Intramembranous Ossification
Neural Crest-Specific Loss of Prkar1a Causes Perinatal Lethality Resulting from Defects in Intramembranous Ossification
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DOI：
10.1210/me.2009-0439
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发表时间：
2010-08-01
影响因子：
--
通讯作者：
Kirschner, Lawrence S.
中科院分区：
文献类型：
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作者：
Jones, Georgette N.;Pringle, Daphne R.;Kirschner, Lawrence S.
颅神经嵴（CNC）在胚胎发生过程中经历了复杂的分子和形态变化，以形成脊椎动物的颅骨，近四分之三的出生缺陷是由颅面发育缺陷引起的。导致CNC分化的分子事件已被广泛研究；然而，camp依赖性蛋白激酶[蛋白激酶A (PKA)]在颅面发育中的作用仅在腭形成中被描述。在这里，我们提供的证据表明，在迁移后的CNC细胞中严格的PKA调控在颅面骨发育过程中是必不可少的。在CNC中，PKA全酶的调控亚基Prkar1a的选择性失活会导致围产儿死亡，导致颅面发育畸形和随后的窒息。此外，CNC间充质细胞的异常分化导致异常的膜内骨化，其特征是在某些区域形成软骨岛，在其他区域骨小梁发生骨溶解并伴有纤维结缔组织稳定。遗传相互作用研究表明，PKA催化亚基C α的遗传减少能够挽救表型，而C β的减少没有影响。总的来说，这些观察结果提供了PKA在颅骨骨化过程中适当调节的重要作用的证据。这一认识可能对理解和治疗颅面出生缺陷具有启示意义。（分子内分泌学24:1559-1568,2010）
The cranial neural crest (CNC) undergoes complex molecular and morphological changes during embryogenesis in order to form the vertebrate skull, and nearly three quarters of all birth defects result from defects in craniofacial development. The molecular events leading to CNC differentiation have been extensively studied; however, the role of the cAMP-dependent protein kinase [ protein kinase A (PKA)] during craniofacial development has only been described in palate formation. Here, we provide evidence that strict PKA regulation in postmigratory CNC cells is essential during craniofacial bone development. Selective inactivation of Prkar1a, a regulatory subunit of the PKA holoenzyme, in the CNC results in perinatal lethality caused by dysmorphic craniofacial development and subsequent asphyxiation. Additionally, aberrant differentiation of CNC mesenchymal cells results in anomalous intramembranous ossification characterized by formation of cartilaginous islands in some areas and osteolysis of bony trabeculae with fibrous connective tissue stabilization in others. Genetic interaction studies revealed that genetic reduction of the PKA catalytic subunit C alpha was able to rescue the phenotype, whereas reduction in C beta had no effect. Overall, these observations provide evidence of the essential role of proper regulation of PKA during the ossification of the bones of the skull. This knowledge may have implications for the understanding and treatment of craniofacial birth defects. (Molecular Endocrinology 24: 1559-1568, 2010)