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Nerve Growth Factor and its Precursor Differentially Regulate Hair Cycle Progression in Mice

Eva M.J. Peters, Sven Hendrix, Greta Gölz, Burghard F. Klapp, Petra C. Arck and Ralf Paus

Biomedical Research Center, Department of Internal Medicine, Psychosomatics, University-Medicine Berlin Charité, Berlin, Germany (EMJP,BFK,PCA); Department of Dermatology, University Hospital Schleswig-Holstein, Campus Lübeck, University of Lübeck, Lübeck, Germany (RP); and Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité, University-Medicine Berlin, Berlin, Germany (SH,GG)

Correspondence to: Dr. Eva Peters, Biomedical Research Center, Room Nr. 2.0549, University Medicine Charité, Virchow Campus, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: eva.peters{at}charite.de

Nerve growth factor (NGF) promotes proliferation via its high affinity receptor (TrkA). Its precursor proNGF promotes apoptosis via the pan-neurotrophin-receptor p75. Recently, we have identified NGF and p75 as important hair growth terminators. However, if proNGF is involved or if NGF can also promote hair growth via TrkA is unclear. By RT-PCR we found that NGF/proNGF mRNA levels peak during early anagen in murine back skin, whereas NGF/proNGF protein levels peak during catagen, indicating high turnover in early anagen and protein accumulation in catagen. By immunohistochemistry, NGF and TrkA are found in the proliferating compartments of the epidermis and hair follicle throughout the cycle. In contrast, strong proNGF is found in the highly differentiated inner root sheath and adjacent to the p75+ regressing epithelial strand in catagen. Commercial 7S NGF, which contains both NGF and proNGF, promotes anagen development in organ-cultured early anagen mouse skin, whereas it promotes catagen development in late anagen skin. Together, our findings suggest an anagen-promoting or anagen-supporting role for NGF/TrkA, and a catagen-promoting role for proNGF/p75 interactions. This has important implications for the future design of specific neurotrophin receptor ligands as novel pharmaceuticals in the modification of tissue remodeling processes such as hair growth or wound healing. (J Histochem Cytochem 54:275–288, 2006)

Key Words: hair cycle • hair follicle • neurotrophin • nerve growth factor • mouse • proNGF • tyrosine kinase A • p75

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