FOLATE AND HOX GENES IN CRANIOFACIAL DEVELOPMENT

描述(由申请者提供)：同源异型盒基因在 颅面发育已经很成熟了。HOX基因表达的变化 导致严重的头面部缺陷，累及颧弓， 腭架形成的原基。最近的证据表明，HOX基因起作用 通过调节细胞在骨骼中的凝聚和生长， 头面部骨骼和上颚。叶酸补充剂可预防 头面部异常，表明与 发育途径。HOX基因和叶酸的共同作用是(I) 它们对细胞增殖的影响，(Ii)它们与维甲酸的关系 酸诱导的致畸作用及其对特定颅面的作用 结构。在这里，我们建议研究的功能关系 叶酸缺乏引起的缺陷与HOX基因介导的缺陷有关。 我们的中心假设是叶酸和HOX基因介导了细胞生长。 颅面结构通过常见的细胞和分子机制。这 将使用两种头面部缺陷的动物模型进行研究：小鼠 在叶酸代谢中进行遗传修饰，而在小鼠中 HOX基因的操控。本研究的具体目的是：(1)界定 细胞分析叶酸和HOX基因在头面部发育中的作用 BrdU掺入法和细胞凋亡率检测细胞增殖。(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的杂交研究 HOXD-4和HOXC-8针对颧弓2。(3)分析HOX 叶酸途径突变体中的基因表达。这些研究使用Folbp1 并将确定哪些叶酸依赖缺陷是由 在特定的头面部区域有特定的HOX基因。(4)确定 叶酸和HOX基因在植物形态发生中的功能关系 头面部缺陷。这将通过基因实现，通过结合 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，以及两者是如何起作用的 这是一种特殊的头面部缺陷的发病机制。 我们的长期目标是整合Hox对基因表达的控制 转录因子与细胞形态发生中的代谢调控 头面部结构。关于基因与基因相互作用的知识 环境因素将是设计治疗策略的重要因素 以及预防头面部缺陷的措施。

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.