p75 Neurotrophin Receptor-Mediated Signaling Promotes Human Hair Follicle Regression (Catagen).
Nerve growth factor (NGF) and its apoptosis-promoting low-affinity receptor (p75NTR) regulate murine hair cycling. However, it is unknown whether human hair growth is also controlled through p75NTR, its high-affinity ligand pro-NGF, and/or the growth-promoting high-affinity NGF receptor tyrosine kinase A (TrkA). In microdissected human scalp anagen hair bulbs, mRNA for NGF, pro-NGF, p75NTR, and TrkA was transcribed. Immunohistomorphometry and in situ hybridization detected strong NGF and pro-NGF expression in terminally differentiating inner root sheath keratinocytes, whereas TrkA was co-expressed with p75NTR in basal and suprabasal outer root sheath keratinocytes. During spontaneous catagen development of organ-cultured human anagen hair follicles, p75NTR mRNA levels rose, and p75NTR and pro-NGF immunoreactivity increased dramatically in involuting compartments primarily devoid of TrkA expression. Here, TUNEL(+) apoptotic cells showed prominent p75NTR expression. Joint pro-NGF/NGF administration inhibited hair shaft elongation and accelerated catagen development in culture, which was antagonized by co-administration of p75NTR-blocking antibodies. In addition, mRNA and protein expression of transforming growth factor-beta2 increased early during spontaneous catagen development, and its neutralization blocked pro-NGF/NGF-dependent hair growth inhibition. Our findings suggest that pro-NGF/NGF interacts with transforming growth factor-beta2 and p75NTR to terminate anagen in human hair follicles, implying that p75NTR blockade may alleviate hair growth disorders characterized by excessive catagen development.
Peters
Eva M J
EM
Biomedical Research Center, Room No. 2.0549, Charité Campus Virchow Hospital, Augustenburger Platz 1, D-13353 Berlin, Germany. eva.peters@charite.de
Stieglitz
Marit G
MG
Liezman
Christiane
C
Overall
Rupert W
RW
Nakamura
Motonobu
M
Hagen
Evelyn
E
Klapp
Burghard F
BF
Arck
Petra
P
Paus
Ralf
R
D017209:Apoptosis / Q000502:physiology; D018859:Hair Follicle / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000378:metabolism; D020932:Nerve Growth Factor / Q000096:biosynthesis; D009924:Organ Culture Techniques; D011498:Protein Precursors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012535:Scalp / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053781:Transforming Growth Factor beta2
D011498:Protein Precursors; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; C061397:pro-nerve growth factor, human; D020932:Nerve Growth Factor; D020917:Receptor, trkA