title: Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as "epitheliotrophins" in murine skin.
abstract: Nerve growth factor (NGF) is produced by keratinocytes and modulates their proliferation and apoptosis. However, it is as yet unknown whether other members of the NGF family of neurotrophins, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), also modulate keratinocyte proliferation in situ. We determined by ELISA and reverse transcriptase-PCR that BDNF, NT-3, and NT-4 are expressed in C57BL/6 mouse skin. By immunofluorescence, the subcutaneous panniculus carnosus muscle and arrector pili muscle showed strong NT-3 immunoreactivity, whereas BDNF-IR was found only in skin nerve bundles. NT-4 immunoreactivity was noted in single epidermal keratinocytes. The high affinity receptor for both BDNF and NT-4, TrkB, was detected in basal and suprabasal epidermal keratinocytes, whereas the high affinity NT-3 receptor, TrkC, was observed in skin nerve bundles. Compared with the corresponding age-matched wild-type mice, BDNF or NT-3-overexpressing transgenic mice showed a significantly increased epidermal thickness and enhanced number of Ki-67-positive (ie, proliferating) epidermal keratinocytes in vivo, whereas the number of these cells was substantially reduced in BDNF knockout mice. In skin organ culture of C57BL/6 mice, BDNF, NT-3, and NT-4 all significantly increased 5-bromo-2'-deoxyuridine incorporation into epidermal keratinocytes. Co-administration of NGF neutralizing antibody failed to abrogate the stimulatory effect of NT-3 on keratinocyte proliferation in skin organ culture. This demonstrates that normal murine epidermal keratinocytes in situ are direct or indirect target cells for these neurotrophins. Therefore, BDNF, NT-3, and NT-4 can also act as "epitheliotrophins" and may thus be intimately involved in the control of epidermal homeostasis.
authors.affiliation: Department of Dermatology, Charité, Humboldt-Universität zu Berlin, Germany.
authors.forename: V A
authors.initials: VA
authors.lastname: Botchkarev
authors.forename: M
authors.initials: M
authors.lastname: Metz
authors.forename: N V
authors.initials: NV
authors.lastname: Botchkareva
authors.forename: P
authors.initials: P
authors.lastname: Welker
authors.forename: M
authors.initials: M
authors.lastname: Lommatzsch
authors.forename: H
authors.initials: H
authors.lastname: Renz
authors.forename: R
authors.initials: R
authors.lastname: Paus
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000235:genetics; D002455:Cell Division; D004797:Enzyme-Linked Immunosorbent Assay; D000078404:Epidermal Cells; D004817:Epidermis / Q000033:anatomy & histology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000166:cytology; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000032:analysis* / Q000235:genetics; D020933:Neurotrophin 3; D009924:Organ Culture Techniques; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019394:Ki-67 Antigen; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012313:RNA; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC; C073922:neurotrophin 4