FOLATE AND HOX GENES IN CRANIOFACIAL DEVELOPMENT

描述（由申请人提供）：同源异型盒基因的关键作用， 颅面发育已经很成熟了Hox基因表达的变化 导致严重的颅面缺损，涉及鳃弓， 腭架形成的原基。最近的证据表明，Hox基因的作用 通过调节骨骼中细胞的凝聚和生长， 颅面骨和上颚叶酸补充剂可预防 颅面异常，表明功能性相互作用， 发展路径。Hox基因和叶酸的共同作用是（i） 它们对细胞增殖的影响，（ii）它们在维甲酸中的参与 酸介导的致畸作用及其对特定颅面的作用 结构.在这里，我们建议调查的功能关系， 由叶酸缺乏引起的缺陷转化为由Hox基因介导的缺陷。 我们的中心假设是叶酸和Hox基因介导细胞生长， 颅面结构通过共同的细胞和分子机制。这 将使用两种具有颅面缺陷的动物模型进行研究：小鼠 在叶酸代谢中有遗传修饰的小鼠， 操纵Hox基因本研究的具体目的是：（1）界定 叶酸和Hox基因在颅颌面发育中作用细胞分析 在BrdU掺入和凋亡测定中的增殖。(2)审查 叶酸途径基因在Hox突变体中的表达。这将由现场完成 条件表达的转基因小鼠胚胎杂交 Hoxd-4和Hoxc-8特异性针对鳃弓2。(3)为了分析霍克斯 叶酸途径突变体的基因表达。这些研究将使用Folbp 1 敲除小鼠，并将确定哪些叶酸依赖性缺陷是由 特定的Hox基因在特定的颅面区域。(4)确定 叶酸和Hox基因在植物形态发生中的功能关系 颅面缺损这将通过基因结合 叶酸途径和Hox基因的突变。这将使我们能够 确定叶酸是否通过Hox基因起作用，反之亦然，以及两者如何起作用 特定颅面缺损的发病机制。 我们的长期目标是整合Hox对基因表达的控制 转录因子和代谢调节在正常形态发生中的作用 颅面结构关于基因与 环境因素对设计治疗策略很重要 以及颅面缺损的预防措施。

DESCRIPTION (provided by applicant): The crucial role of homeobox genes in craniofacial development is well established. Changes in Hox gene expression result in severe craniofacial defects, involving the branchial arches, the primordia for palate shelf formation. Recent evidence shows that Hox genes act through regulating cell condensation and growth m the skeleton, the craniofacial bones and the palate. Folate supplementation protects against craniofacial abnormalities, indicating a functional interaction with developmental pathways. Common to the action of Hox genes and folate are (i) their effects on cell proliferation, (ii) their involvement m Retinoic Acid-mediated teratogenesis and (iii) their actions on specific craniofacial structures. We here propose to investigate the functional relationship of defects induced by folate-deficiency to those mediated by Hox genes. Our central hypothesis is that folate and Hox genes mediate cell growth in craniofacial structures through common cellular and molecular mechanisms. This will be investigated using two animal models with craniofacial defects: mice with genetic modifications in folate metabolism, and mice with genetic manipulations in Hox genes. The specific aims of this study are: (1) To define the role of folate and Hox genes in craniofacial development by analyzing cell proliferation in BrdU incorporation and apoptosis assays. (2) To examine the expression of folate pathway genes m Hox mutants. This will be done by in situ hybridization on embryos from transgenic mice with conditional expression of Hoxd-4 and Hoxc-8 directed specifically to branchial arch 2. (3) To analyze Hox gene expression in folate pathway mutants. These studies will use Folbp1 knockout mice and will identify which folate-dependent defects are mediated by particular Hox genes in specific craniofacial regions. (4) To determine the functional relationship of folate and Hox genes in the morphogenesis of craniofacial defects. This will be accomplished genetically, by combining mutations in the folate pathway and those in Hox genes. This will allow us to ascertain whether folate acts through Hox genes or vice versa, and how both act m the pathogenesis of specific craniofacial defects. Our long-term goal is to integrate the control of gene expression by Hox transcription factors and metabolic regulation m the proper morphogenesis of craniofacial structures. Knowledge about the interactions of genes with environmental factors will be important for designing therapeutic strategies and preventive measures against craniofacial defects.