title: Lhx2 is a direct NF-κB target gene that promotes primary hair follicle placode down-growth.
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.
authors.affiliation: Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Tomann
authors.affiliation: Department of Dermatology, University of Münster, Münster 48149, Germany Dermatological Science Research Group, Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Millar
authors.affiliation: Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.affiliation: Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin 13092, Germany rschmidt@mdc-berlin.de.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018859:Hair Follicle / Q000196:embryology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000235:genetics*
chemical_list: D015820:Cadherins; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; C498144:Rela protein, mouse; C509042:Tgfb2 protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2
keywords: Cell migration; E-cadherin; EDA-A1; EDAR; Embryo; Hair follicle; LHX2; Mouse; NF-κB; Placode; Stem cell; TGFβ2