Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin

Vladimir A. Botchkarev, Martin Metz, Natalia V. Botchkareva, Pia Welker, Marek Lommatzsch, Harald Renz, Ralf Paus

Research output: Contribution to journalArticle

59 Citations (Scopus)

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 pill 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.

Original languageEnglish (US)
Pages (from-to)557-572
Number of pages16
JournalLaboratory Investigation
Volume79
Issue number5
StatePublished - May 1 1999
Externally publishedYes

Fingerprint

Neurotrophin 3
Brain-Derived Neurotrophic Factor
Keratinocytes
Skin
Nerve Growth Factor
Organ Culture Techniques
Nerve Growth Factors
Inbred C57BL Mouse
trkC Receptor
trkB Receptor
Muscles
neurotrophin 4
Bromodeoxyuridine
Neutralizing Antibodies
Reverse Transcriptase Polymerase Chain Reaction
Knockout Mice
Transgenic Mice
Fluorescent Antibody Technique
Homeostasis
Cell Count

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Botchkarev, V. A., Metz, M., Botchkareva, N. V., Welker, P., Lommatzsch, M., Renz, H., & Paus, R. (1999). Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin. Laboratory Investigation, 79(5), 557-572.

Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin. / Botchkarev, Vladimir A.; Metz, Martin; Botchkareva, Natalia V.; Welker, Pia; Lommatzsch, Marek; Renz, Harald; Paus, Ralf.

In: Laboratory Investigation, Vol. 79, No. 5, 01.05.1999, p. 557-572.

Research output: Contribution to journalArticle

Botchkarev, VA, Metz, M, Botchkareva, NV, Welker, P, Lommatzsch, M, Renz, H & Paus, R 1999, 'Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin', Laboratory Investigation, vol. 79, no. 5, pp. 557-572.
Botchkarev VA, Metz M, Botchkareva NV, Welker P, Lommatzsch M, Renz H et al. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin. Laboratory Investigation. 1999 May 1;79(5):557-572.
Botchkarev, Vladimir A. ; Metz, Martin ; Botchkareva, Natalia V. ; Welker, Pia ; Lommatzsch, Marek ; Renz, Harald ; Paus, Ralf. / Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as 'Epitheliotrophins' in murine skin. In: Laboratory Investigation. 1999 ; Vol. 79, No. 5. pp. 557-572.
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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 pill 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.",
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