Abstract
Skin appendages such as teeth and hair share several common signaling pathways. The nuclear factor I C (NFI-C) transcription factor has been implicated in tooth development, but a potential role in hair growth had not been assessed. In this study we found that NFI-C regulates the onset of the hair growth cycle. NFI-C(-/-) mice were delayed in the transition from the telogen to anagen phase of the hair follicle cycle after either experimental depilation or spontaneous hair loss. Lack of NFI-C resulted in delayed induction of the sonic hedgehog, Wnt5a, and Lef1 gene expression, which are key regulators of the hair follicle growth initiation. NFI-C(-/-) mice also showed elevated levels of transforming growth factor β1 (TGF-β1), an inhibitor of keratinocyte proliferation, and of the cell cycle inhibitor p21 at telogen. Reduced expression of Ki67, a marker of cell proliferation, was noted at the onset of anagen, indicating impaired activation of the hair progenitor cells. These findings implicate NFI-C in the repression of TGF-β1 signaling during telogen stage, resulting in the delay of progenitor cell proliferation and hair follicle regeneration in NFI-C-deficient mice. Taken together with prior observations, these findings also designate NFI-C as a regulator of adult progenitor cell proliferation and of postnatal tissue growth or regeneration.
Highlights
Crowns but lack roots [7]
We have shown that nuclear factor I C (NFI-C) deficiency affects the normal progression of the skin wound healing process, which has been linked to altered platelet-derived growth factor (PDGF) and TGF- signaling in the knockout animals [9]
Identification of a Delayed Hair Growth Phenotype in NFICϪ/Ϫ Mice—Hair barbering of a litter is a stress-related disorder observed with some inbred mouse lines that appears as a loss of hair of all pups as a consequence of an over-grooming behavior by the mother
Summary
Crowns but lack roots [7]. These abnormalities have been associated with a decreased proliferation of NFI-C-lacking dental cells due to the overexpression of transforming growth factor 1 (TGF-1) [8]. Molecular interactions between the dermal papilla and the epithelial stem cells of the bulge are believed to be responsible for activation of their proliferation, leading to the transition from telogen to anagen phase. The stimulation of bulge stem cells gives rise to rapidly dividing cells that migrate to the matrix [18] These keratinocyte progenitor cells will undergo a finite number of divisions to generate the lower part of the follicle, where their terminal differentiation will produce the IRS and the hair shaft [19]. High levels of TGF-1 and cell cycle inhibitor p21/WAF1/CIP1 (p21) and decreased expression of Ki67, a marker of cell proliferation, were observed at the telogen and telogen-anagen transition in NFI-CϪ/Ϫ animals Taken together, these results indicate that loss of NFI-C leads to a persistent activation of the TGF- pathway at telogen that induces a delay in Shh and Wnt/-catenin/Lef-1 signaling activation and keratinocyte proliferation
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