Whiting J
Department of Craniofacial Development, UMDS, Guy's Hospital, London, UK.
Mutat Res. 1997 Dec 12;396(1-2):97-112. doi: 10.1016/s0027-5107(97)00177-2.
In this paper I have tried to bring together work that highlights the role of homeobox genes in generating craniofacial form. I review both normal and disrupted embryogenesis and ask whether mis-expression of the homeobox genes outside their normal domains could be contributing to congenital facial abnormalities arising from either genetic or teratogenic actions. Experimentally generated transgenic mice carrying loss- or gain-of-function mutations in homeobox genes, in combination with their normal expression patterns, have allowed us to compile and test models of embryonic specification based around a Hox/homeobox code. These models form the basis on which the functional questions are considered. There are four major sections covering different experimental approaches designed to ectopically induce homeobox genes in the head. Transgenic mice, where heterologous promoters drive a given Hox gene in the head, have shown that the more posteriorly expressed Hox genes tend to have a significant effect only on the skull bones of mesodermal origin whereas those normally expressed more anteriorly, in the hindbrain and branchial arches, can affect more anterior branchial arch and neural crest-derived structures. Manipulation experiments which can induce homeobox genes in small, localised regions of the facial precursors show clear and dramatic effects of this expression on facial development. Null mutations in predicted repressors of Hox gene expression, however, do not appear to give rise to substantial craniofacial abnormalities. Retinoic acid, on the other hand, is well known for its teratogenic actions and its ability to induce Hox gene expression. Evidence is now accumulating that at least some of its teratogenic actions may be mediated by its regulation of the Hox and other homeobox genes in the head.
在本文中，我试图汇集一些突出同源框基因在生成颅面形态中作用的研究工作。我回顾了正常和异常的胚胎发育过程，并探讨同源框基因在其正常表达域之外的异常表达是否可能导致由遗传或致畸作用引起的先天性面部异常。通过实验构建的携带同源框基因功能缺失或功能获得突变的转基因小鼠，结合它们的正常表达模式，使我们能够编制并测试基于Hox/同源框编码的胚胎特化模型。这些模型构成了思考功能问题的基础。本文有四个主要部分，涵盖了旨在异位诱导头部同源框基因的不同实验方法。转基因小鼠中，异源启动子在头部驱动特定的Hox基因表达，结果表明，表达位置越靠后的Hox基因往往仅对中胚层来源的颅骨有显著影响，而那些通常在更靠前位置（后脑和鳃弓）表达的基因，则可影响更靠前的鳃弓和神经嵴衍生结构。在面部前体的小局部区域诱导同源框基因表达的操作实验表明，这种表达对面部发育有明显且显著的影响。然而，Hox基因表达预测抑制因子的无效突变似乎并未导致明显的颅面异常。另一方面，视黄酸以其致畸作用及其诱导Hox基因表达的能力而闻名。现在越来越多的证据表明，其至少部分致畸作用可能是通过对头部Hox基因和其他同源框基因的调控介导的。
