| Popis: |
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-{kappa}B inhibition. To identify additional NF-{kappa}B target genes, we developed a novel method to isolate and transcriptionally profile primary HF placodes with active NF-{kappa}B signaling. In parallel, we compared gene expression at the same developmental stage in NF-{kappa}B-deficient embryos and controls. This uncovered novel NF-{kappa}B 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{beta}2 signaling is impaired in NF-{kappa}B-deficient and Lhx2 knockout embryos and that exogenous TGF{beta}2 rescues the HF phenotypes in Lhx2 knockout skin explants, indicating that it operates downstream of LHX2. These findings identify a novel NF-{kappa}B/LHX2/TGF{beta}2 signaling axis that is crucial for primary HF morphogenesis, which may also function more broadly in development and disease. |
