Lhx2 is a direct NF-κB target gene that promotes primary hair follicle placode down-growth
Lhx2 is a direct NF-κB target gene that promotes primary hair follicle placode down-growth
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DOI：
10.1242/dev.130898
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发表时间：
2016-05-01
期刊：
影响因子：
4.6
通讯作者：
Schmidt-Ullrich, Ruth
中科院分区：
文献类型：
--
作者：
Tomann, Philip;Paus, Ralf;Schmidt-Ullrich, Ruth
在缺乏转录因子核因子κ B（NF-κ B）活性的小鼠表皮中，初级毛囊（HF）前基板形成开始，而没有进展到适当的基板。NF-κ B在HF发展的早期调节WNT和SHH信号传导，但这不能完全解释NF -κ B抑制后观察到的表型。为了鉴定另外的NF -κ B靶基因，我们开发了一种新的方法来分离和转录分析具有活性NE-κ B信号传导的原发性HF基板。同时，我们比较了NF-κ B缺陷胚胎和对照组在相同发育阶段的基因表达。这揭示了在引发HF基板向下生长中具有潜在作用的新的NF -κ B靶基因。重要的是，我们确定Lhx 2（编码LIM/同源框转录因子）作为直接NF-κ B B靶基因，其缺失复制了NF-κ B缺陷胚胎中观察到的表型子集。Lhx 2和Tgfb 2基因敲除胚胎在HF发育中表现出非常相似的异常，包括卵泡向下生长所需的E-钙粘蛋白抑制失败。我们表明TGF β 12信号传导在NF-κ B缺陷和Lhx 2敲除胚胎中受损，并且外源性TGF β 112挽救了Lhx 2敲除皮肤外植体中的HF表型，表明其在Lhx 2下游起作用。这些发现鉴定了一种新的NF-κ B/LHX 2/TGF β 32信号传导轴，其对原发性HF形态发生至关重要，其也可能在发育和疾病中发挥更广泛的作用。
In the epidermis of mice lacking transcription factor nuclear factor kappa B (NF-kappa B) activity, primary hair follicle (HF) pre-placode formation is initiated without progression to proper placodes. NF-kappa B modulates WNT and SHH signaling at early stages of HF development, but this does not fully account for the phenotypes observed upon NF -KB inhibition. To identify additional NF -KB target genes, we developed a novel method to isolate and transcriptionally profile primary HF placodes with active NE-kappa B signaling. In parallel, we compared gene expression at the same developmental stage in NF-KB-deficient embryos and controls. This uncovered novel NF -KB target genes with potential roles in priming HF placodes for down growth. Importantly, we identify Lhx2 (encoding a LIM/homeobox transcription factor) as a direct NF-kappa B target gene, loss of which replicates a subset of phenotypes seen in NF-kappa B-deficient embryos. Lhx2 and Tgfb2 knockout embryos exhibit very similar abnormalities in HF development, including failure of the E-cadherin suppression required for follicle down-growth. We show that TGF)32 signaling is impaired in NF-kappa B-deficient and Lhx2 knockout embryos and that exogenous TGE112 rescues the HF phenotypes in Lhx2 knockout skin explants, indicating that it operates downstream of LHX2. These findings identify a novel NF-KB/LHX2/TGF)32 signaling axis that is crucial for primary HF morphogenesis, which may also function more broadly in development and disease.