Underhill T M, Sampaio A V, Weston A D
School of Dentistry, Faculty of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Novartis Found Symp. 2001;232:171-85; discussion 185-8. doi: 10.1002/0470846658.ch12.
Metabolites of vitamin A, including retinoic acid (RA), comprise a class of molecules known to be important in development and homeostasis. RA functions through a class of nuclear hormone receptors, the RA receptors (RARs), to regulate gene transcription. In the developing mammalian limb, RA affects the differentiation of many cell lineages, including those of the chondrogenic lineage. In excess, RA is a potent teratogen, causing characteristic skeletal defects in a stage- and dose-dependent manner. Genetic analysis has shown that the absence of RARs leads to severe deficiencies in cartilage formation at certain anatomical locations while promoting ectopic cartilage formation at other sites. Expression of either a dominant-negative or a weak constitutively active RAR in the developing limbs of transgenic mice adversely affects chondrogenesis leading to skeletal malformations. Together, these results show that RAR-mediated signalling plays a fundamental role in skeletogenesis. This chapter will focus on the function of RARs in regulating chondroblast differentiation and the contribution of RA signalling to appositional and longitudinal growth of the skeletal primordia.
维生素A的代谢产物，包括视黄酸（RA），构成了一类已知在发育和体内平衡中起重要作用的分子。RA通过一类核激素受体，即RA受体（RARs）发挥作用，以调节基因转录。在发育中的哺乳动物肢体中，RA影响许多细胞谱系的分化，包括软骨形成谱系的细胞。过量的RA是一种强效致畸剂，以阶段和剂量依赖的方式导致特征性骨骼缺陷。遗传分析表明，RARs的缺失会导致某些解剖位置的软骨形成严重缺陷，同时促进其他部位的异位软骨形成。在转基因小鼠发育中的肢体中表达显性负性或弱组成型活性RAR会对软骨形成产生不利影响，导致骨骼畸形。总之，这些结果表明RAR介导的信号传导在骨骼生成中起基本作用。本章将重点关注RARs在调节成软骨细胞分化中的功能以及RA信号传导对骨骼原基的附加生长和纵向生长的贡献。
