Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Curr Top Dev Biol. 2012;98:35-63. doi: 10.1016/B978-0-12-386499-4.00002-1.
The Grainy head (Grh) family of transcription factors is characterized by a unique DNA-binding domain that binds to a conserved consensus sequence. Nematodes and flies have a single grh gene, whereas mice and humans have evolved three genes encoding Grainy head-like (Grhl) factors. We review the biological function of Grh in different animals and the mechanisms modulating its activity. grh and grhl genes play a remarkably conserved role in epithelial organ development and extracellular barrier repair after tissue damage. Recent studies in flies and vertebrates suggest that Grh factors may be primary determinants of cell adhesion and epithelial tissue formation. Grh proteins can dimerize and act as activators or repressors in different developmental contexts. In flies, tissue-specific, alternative splicing generates different Grh isoforms with different DNA-binding specificities and functions. Grh activity is also modulated by receptor tyrosine kinases: it is phosphorylated by extracellular signal regulated kinase, and this phosphorylation is selectively required for epidermal barrier repair. Two mechanisms have been proposed to explain the repressive function of Grh on target gene transcription. First, Grh can target the Polycomb silencing complex to specific response elements. Second, it can directly compete for DNA binding with transcriptional activators. Understanding the molecular mechanisms of gene regulation by Grh factors is likely to elucidate phylogenetically conserved mechanisms of epithelial cell morphogenesis and regeneration upon tissue damage.
颗粒头（Grh）转录因子家族的特征是具有独特的 DNA 结合域，该域结合到保守的共识序列。线虫和果蝇只有一个 grh 基因，而小鼠和人类则进化出了三个编码 Grainy head-like（Grhl）因子的基因。我们综述了 Grh 在不同动物中的生物学功能及其调节其活性的机制。grh 和 grhl 基因在上皮器官发育和组织损伤后细胞外屏障修复中起着非常保守的作用。最近在果蝇和脊椎动物中的研究表明，Grh 因子可能是细胞黏附和上皮组织形成的主要决定因素。Grh 蛋白可以二聚化，并在不同的发育环境中充当激活子或抑制子。在果蝇中，组织特异性的选择性剪接产生具有不同 DNA 结合特异性和功能的不同 Grh 同工型。Grh 的活性也受受体酪氨酸激酶调节：它被细胞外信号调节激酶磷酸化，这种磷酸化选择性地需要表皮屏障修复。提出了两种机制来解释 Grh 对靶基因转录的抑制功能。首先，Grh 可以将 Polycomb 沉默复合物靶向特定的反应元件。其次，它可以直接与转录激活剂竞争 DNA 结合。了解 Grh 因子对基因调控的分子机制可能阐明组织损伤后上皮细胞形态发生和再生的进化保守机制。
