Lhx2 is a direct NF-κB target gene that promotes primary hair follicle placode down-growth

Philip Tomann, Ralf Paus, Sarah E Millar, Claus Scheidereit, Ruth Schmidt-Ullrich

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Abstract

In the epidermis of mice lacking transcription factor nuclear factor-kappa B (NF-κB) activity, primary hair follicle (HF) pre-placode formation is initiated without progression to proper placodes. NF-κB modulates WNT and SHH signaling at early stages of HF development, but this does not fully account for the phenotypes observed upon NF-κB inhibition. To identify additional NF-κB target genes, we developed a novel method to isolate and transcriptionally profile primary HF placodes with active NF-κB signaling. In parallel, we compared gene expression at the same developmental stage in NF-κB-deficient embryos and controls. This uncovered novel NF-κB 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-κB target gene, loss of which replicates a subset of phenotypes seen in NF-κB-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 TGFβ2 signaling is impaired in NF-κB-deficient and Lhx2 knockout embryos and that exogenous TGFβ2 rescues the HF phenotypes in Lhx2 knockout skin explants, indicating that it operates downstream of LHX2. These findings identify a novel NF-κB/LHX2/TGFβ2 signaling axis that is crucial for primary HF morphogenesis, which may also function more broadly in development and disease.

Original languageEnglish
Pages (from-to)1512-22
Number of pages11
JournalDevelopment (Cambridge, England)
Volume143
Issue number9
Early online date7 Mar 2016
DOIs
Publication statusPublished - 3 May 2016

Keywords

  • Animals
  • Cadherins/metabolism
  • Cell Differentiation/genetics
  • Cell Movement/genetics
  • Embryo, Mammalian/metabolism
  • Gene Expression Regulation, Developmental/genetics
  • Hair Follicle/embryology
  • LIM-Homeodomain Proteins/genetics
  • Mice
  • Mice, Knockout
  • Organ Culture Techniques
  • Organogenesis/genetics
  • Receptors, Transforming Growth Factor beta/metabolism
  • Transcription Factor RelA/genetics
  • Transcription Factors/genetics
  • Transforming Growth Factor beta2/genetics

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