| |
Department
of Dermatology (VAB, MM, NVB, PW, RP), and Institute of Laboratory Medicine
and Pathobiochemistry (ML, HR), Charité, Humboldt-Universität
zu Berlin, Berlin, Germany |
| |
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. (Lab Invest, 79:557-572).
|
