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 factorkappa 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 downgrowth. 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.

Hierarchical patterning modes orchestrate hair follicle morphogenesis

“…This expression is consistent with widespread SMAD2 phosphorylation in early dermal fibroblasts, becoming focussed in incipient dermal condensates (Fig 6D) [59]. To test whether TGFβ2 can attract mouse dermal mesenchymal cells, as previously reported for chicken mesenchyme [60], we applied TGFβ2-coated beads to skin and detected a strong accumulation of cells around the bead (Fig 6E).…”

An updated classification of hair follicle morphogenesis

“…Intriguingly, Cxcr4 expression wanes as the Pc matures, and is completely lost by Stage 4 HF morphogenesis, although the gene, itself, appears dispensable for HF morphogenesis . Shh, Pcad and Lhx2, a downstream target of Edar, are now expressed within these basal matrix progenitors. At this stage, Sox9 + suprabasal HFSC precursors are specified during perpendicular asymmetric cell divisions of Shh‐expressing basal Pc progenitors with high Wnt signalling activity (Figures and , Stage 3), and, once suprabasal, have very low levels of Wnt signalling.…”

“…Furthermore, many emerging technologies such as live imaging, multicolour fluorescent labelling and isolation of distinct cell types from specific stages, as well as high sensitivity transcriptomics at both the population and single‐cell level, have enabled a more fine‐toothed dissection of the cellular and molecular dynamics of HF morphogenesis. Such advances have permitted the definition of molecular signatures of Pc and DC, and neighbouring cell types, as well as identified migration as the main cellular mechanism of Pc and DC formation . They have also allowed for the discovery of precursors to the Pc (pre‐Pc), multipotent fibroblasts that give rise to the DC and the fated precursors of DC (pre‐DC), by their molecular properties and prior to identifiable changes in cell morphologies and arrangement.…”

Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

“…Yet, we did not observe any alopecia in Ednra Y129F/+ or Ednra Y129F/Y129F mice as reported for MFDA-affected patients. Inherited alopecia is correlated with a number of abnormalities including hormonal factors, alterations of gene transcription factors, impaired morphogenesis of hair follicles, and other cell signaling pathways (Tomann et al 2016). However, how these and other underlying factors are exactly linked to healthy or aberrant morphology, hair follicle cycling, and subsequently hair loss is still unclear.…”