Frontonasal process-specific disruption of AP-2α results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects
Frontonasal process-specific disruption of AP-2α results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects
复制标题
DOI：
10.1016/j.ydbio.2003.10.033
复制
发表时间：
2004-03-01
影响因子：
2.7
通讯作者：
Williams, T
中科院分区：
文献类型：
--
作者：
Nelson, DK;Williams, T
脊椎动物颅穹和颅面复合体的大部分骨骼通过膜内骨化发育，并通过纤维缝合线分离，在生长刺激下进行成骨分化。颅缝闭合是一种常见的人类先天性缺陷，由颅骨缝合线内过早的骨融合引起，并引起无数的并发症，包括智力迟钝和颅面异常。据报道，在一些颅缝闭合的病例中，面缝闭合会导致面中部发育不全，但大多数研究都集中在颅穹窿缝合上。在本研究中，我们通过组织特异性消除AP-2alpha转录因子，建立了额鼻缝合缝膜紧闭和面中发育不全的小鼠模型。我们在此报告了新一代AP-2CRE，这是一个额鼻过程（FNP）和肢体特异性的CRE重组酶等位基因，由人类AP-2alpha启动子和增强子元件指导。我们将ap - 2re系与条件AP-2alpha系结合，在FNP和肢体中产生了新的额鼻敲除（FKO）突变体，该突变体缺乏AP-2alpha。FKO小鼠在出生后的第15天表现出缩短的鼻子和宽的眼睛。FKO鼻部最突出的缺陷是(1)鼻前缝合线内缺乏生长，(2)鼻部血管系统减少。在FKO鼻骨和缝合线、鼻腔软骨和骨突起以及嗅上皮中观察到其他缺陷。FKO小鼠模型的特征是面部中部生长异常的独特组合，并提供了AP-2alpha对适当的出生后颅面形态发生至关重要的第一个证据。(C) 2003 Elsevier Inc.版权所有。
A majority of the bones of the vertebrate cranial vault and craniofacial complex develop via intramembranous ossification, and are separated by fibrous sutures that undergo osteogenic differentiation in response to growth stimuli. Craniosynostosis is a common human birth defect that results from the premature bony fusion within skull sutures, and causes a myriad of complications including mental retardation and craniofacial anomalies. Synostosis of facial sutures has been reported to cause midfacial hypoplasia in some craniosynostosis cases, but most studies focus on cranial vault sutures. In this study, we have generated a mouse model of frontonasal suture synostosis and midfacial hypoplasia through the tissue-specific elimination of the AP-2alpha transcription factor. We report here the generation AP-2CRE, a frontonasal process (FNP)- and limb-specific CRE recombinase allele that is directed by human AP-2alpha promoter and enhancer elements. We used the AP-2CRE line in combination with the conditional AP-2alpha line to produce a new frontonasal knockout (FKO) mutant that lacks AP-2alpha in the FNP and limbs. FKO mice exhibit shortened snouts and wide-set eyes that become apparent at postnatal day 15. The most prominent defects in FKO snouts are (1) a lack of growth within the frontonasal sutures, and (2) a reduction in the snout vasculature. Additional defects are observed in the FKO nasal bones and sutures, the nasal cavity cartilage and bony projections, and the olfactory epithelium. The characteristics of the FKO mouse model are a unique combination of midfacial growth anomalies, and provide the first evidence that AP-2alpha is essential for appropriate postnatal craniofacial morphogenesis. (C) 2003 Elsevier Inc. All rights reserved.