Brewer Stephanie, Feng Weiguo, Huang Jian, Sullivan Shelley, Williams Trevor
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
Dev Biol. 2004 Mar 1;267(1):135-52. doi: 10.1016/j.ydbio.2003.10.039.
The AP-2alpha transcription factor is required for multiple aspects of vertebrate development and mice lacking the AP-2alpha gene (tcfap2a) die at birth from severe defects affecting the head and trunk. Several of the defects associated with the tcfap2a-null mutation affect neural crest cell (NCC) derivatives including the craniofacial skeleton, cranial ganglia, and heart outflow tract. Consequently, there is considerable interest in the role of AP-2alpha in neural crest cell function in development and evolution. In addition, the expression of the AP-2alpha gene is utilized as a marker for premigratory and migratory neural crest cells in many vertebrate species. Here, we have specifically addressed how the presence of AP-2alpha in neural crest cells affects development by creating a conditional (floxed) version of tcfap2a which has subsequently been intercrossed with mice expressing Cre recombinase under the control of Wnt1 cis-regulatory sequences. Neural crest-specific disruption of tcfap2a results in frequent perinatal lethality associated with neural tube closure defects and cleft secondary palate. A small but significant fraction of mutant mice can survive into adulthood, but have retarded craniofacial growth, abnormal middle ear development, and defects in pigmentation. The phenotypes obtained confirm that AP-2alpha directs important aspects of neural crest cell function. At the same time, we did not observe several neurocristopathies affecting the head and heart that might be expected based on the phenotype of the AP-2alpha-null mouse. These results have important implications for the evolution and function of the AP-2 gene family in both the neural crest and the vertebrate embryo.
AP-2α转录因子是脊椎动物发育多个方面所必需的，缺乏AP-2α基因（tcfap2a）的小鼠在出生时因影响头部和躯干的严重缺陷而死亡。与tcfap2a基因敲除突变相关的一些缺陷影响神经嵴细胞（NCC）衍生物，包括颅面骨骼、颅神经节和心脏流出道。因此，人们对AP-2α在神经嵴细胞功能在发育和进化中的作用非常感兴趣。此外，在许多脊椎动物物种中，AP-2α基因的表达被用作迁移前和迁移中的神经嵴细胞的标志物。在这里，我们通过创建一个条件性（floxed）版本的tcfap2a，专门研究了神经嵴细胞中AP-2α的存在如何影响发育，该版本随后与在Wnt1顺式调控序列控制下表达Cre重组酶的小鼠进行了杂交。tcfap2a的神经嵴特异性破坏导致与神经管闭合缺陷和腭裂相关的频繁围产期死亡。一小部分但相当数量的突变小鼠可以存活到成年，但有颅面生长迟缓、中耳发育异常和色素沉着缺陷。所获得的表型证实AP-2α指导神经嵴细胞功能的重要方面。同时，我们没有观察到基于AP-2α基因敲除小鼠的表型可能预期的几种影响头部和心脏的神经嵴病。这些结果对AP-2基因家族在神经嵴和脊椎动物胚胎中的进化和功能具有重要意义。
