Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.
Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.
复制标题
DOI：
10.1530/joe-13-0212
复制
发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Haussler MR
中科院分区：
文献类型：
--
作者：
Hsieh JC;Estess RC;Kaneko I;Whitfield GK;Jurutka PW;Haussler MR
维生素D受体（VDR），而不是其激素配体，1，25-二羟基维生素D3（1，25 D），是哺乳动物毛发周期进展所必需的。我们研究了与毛发周期信号传导相关的三个基因，DKKL 1（Soggy），SOSTDC 1（Wise）和HR（Hairless），以确定它们的表达是否受VDR和/或其1，25 D配体的调节。在原代人类和CCD-1106 KERTr角质形成细胞中，DKKL 1 mRNA被1，25 D抑制49-72%;在小鼠Soggy中，在−9590 bp处鉴定出功能性维生素D反应元件（VDRE）。类似地，在KERTr和原代人角质形成细胞中，SOSTDC 1 mRNA被1，25 D抑制41-59%;在人Wise中，功能性VDRE位于−6215 bp处。相比之下，在原代人类和KERTr角质形成细胞中，HR mRNA被1，25 D上调1.56-2.77倍;在人类Hairless基因中鉴定出由3个核苷酸（DR 3）分隔的不完全直接重复序列组成的VDRE（TGGTGAgtgAGGACA），其在−7269 bp处介导显著诱导，即使在不存在1，25 D配体的情况下。与此同时，在人HR基因+1304 bp处鉴定了DR 4甲状腺激素应答元件TGGTGGGccAGGACA，其赋予T3非依赖性转录激活。由于甲状腺激素受体控制中枢神经系统中的HR表达，而VDR与HR辅阻遏物特异性地在皮肤中协同作用，因此提出了一种模型，其中未配体的VDR上调HR的表达，其基因产物充当下游共调节剂以反馈阻遏DkkL 1和SOSTDC 1，导致BMP和Wnt信号的整合以驱动哺乳动物毛发周期和/或影响表皮功能。
The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine if their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49–72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at −9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41–59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at −6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56–2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by 3 nucleotides (DR3) was identified at −7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred T3-independent transcriptional activation. Because thyroid hormone receptor controls HR expression in the central nervous system, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback repress DkkL1 and SOSTDC1, resulting in integration of BMP and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.