Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia.
Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia.
复制标题
DOI：
--
复制
发表时间：
2001-05
期刊：
影响因子：
4.6
通讯作者：
A. Tkatchenko;R. Visconti;L. Shang;T. Papenbrock;N. Pruett;T. Ito;M. Ogawa;A. Awgulewitsch
中科院分区：
文献类型：
--
作者：
A. Tkatchenko;R. Visconti;L. Shang;T. Papenbrock;N. Pruett;T. Ito;M. Ogawa;A. Awgulewitsch
要研究HOX基因在皮肤和毛发正常和病理发育中的作用，需要在基因定义的动物模型中识别下游靶基因。我们发现，在毛囊角质形成细胞中过度表达Hoxc13的转基因小鼠会患上脱发，并伴有类似鱼鳞病的进行性病理皮肤状况。对这些小鼠出生后皮肤差异基因表达的大规模分析发现，16个以前未知的基因和13个已知基因是假定的Hoxc13靶标。这些靶标中的大多数是下调的，属于编码毛发特异性角蛋白相关蛋白(KAPS)的基因亚群。利用小鼠仓鼠辐射杂交面板进行的基因组图谱显示，这些基因位于小鼠16号染色体上与人类染色体21q22.11保守连锁的一个新的KAP基因簇中。此外，在过度表达Hoxc13的小鼠中进行Hoxc13/LacZ报告基因分析所获得的数据表明，Hoxc13表达水平的负自我调节反馈控制，从而为阐明目前未知的调控HOX基因表达数量水平所需的机制提供了一个切入点。综上所述，这些结果为理解Hoxc13在毛发生长和发育中作用的分子机制提供了一个框架。
Studying the roles of Hox genes in normal and pathological development of skin and hair requires identification of downstream target genes in genetically defined animal models. We show that transgenic mice overexpressing Hoxc13 in differentiating keratinocytes of hair follicles develop alopecia, accompanied by a progressive pathological skin condition that resembles ichthyosis. Large-scale analysis of differential gene expression in postnatal skin of these mice identified 16 previously unknown and 13 known genes as presumptive Hoxc13 targets. The majority of these targets are downregulated and belong to a subgroup of genes that encode hair-specific keratin-associated proteins (KAPs). Genomic mapping using a mouse hamster radiation hybrid panel showed these genes to reside in a novel KAP gene cluster on mouse chromosome 16 in a region of conserved linkage with human chromosome 21q22.11. Furthermore, data obtained by Hoxc13/lacZ reporter gene analysis in mice that overexpress Hoxc13 suggest negative autoregulatory feedback control of Hoxc13 expression levels, thus providing an entry point for elucidating currently unknown mechanisms that are required for regulating quantitative levels of Hox gene expression. Combined, these results provide a framework for understanding molecular mechanisms of Hoxc13 function in hair growth and development.