A role for p75 neurotrophin receptor in the control of apoptosis‐driven hair follicle regression

Botchkarev, Vladimir A.; Botchkareva, Natalia V.; Albers, Kathryn M.; Chen, Ling Hong; Welker, Pia; Paus, Ralf

doi:10.1096/fj.99-0930com

Cited by 97 publications

(100 citation statements)

References 67 publications

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“…Further, NGF can significantly enhance the percentage of hair follicles in advanced catagen stages. 27,28,50 This is in line with our present in vivo observations of premature catagen development in stressed mice, where levels of NGF are up-regulated.…”

Section: Discussionsupporting

confidence: 90%

“…24 The presence of NGF in murine skin has recently been described, 25,26 alluding to its involvement in the control of apoptosis-driven hair follicle regression (catagen). [27][28][29] Specifically, selected NTs accelerate catagen most likely by stimulating the p75NTR receptor, which is expressed in the regressing outer root sheath (ORS) and is known to mediate apoptosis when activated alone. 27,30 -32 Based on these recent insights into the role of NTs in hair growth control and the central role of NGF in stressinduced neurogenic inflammation, we hypothesized that NGF production in the skin is up-regulated following stress exposure, which in turn promotes up-regulation and release of neuropeptides, eg, SP from sensory cfibers.…”

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confidence: 99%

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Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

Peters

Handjiski

Kuhlmei

et al. 2004

The American Journal of Pathology

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114

161

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Recently, we have revealed the existence of a "brainhair follicle axis" in murine skin and have identified the neuropeptide substance P (SP) as a key mediator of stress-induced hair growth inhibition in vivo. Published evidence suggests that increased numbers of SP-immunoreactive sensory fibers, as seen in the dermis of stressed mice in anagen-catagen transition, are a result of transient high levels of nerve growth factor (NGF). Thus, we now aimed at dissecting the role of NGF in stress-triggered hair growth termination in our murine model. By real time PCR and immunohistochemistry, stress-exposed mice showed an up-regulation of NGF and its low-affinity receptor p75NTR; the NGF high-affinity receptor TrkA was moderately down-regulated. On neutralization of NGF, premature onset of catagen, apoptosis, and increased number/ activation of perifollicular mast cells and antigen-presenting cells, which reflects the skin response to stress, was significantly abrogated. Stress or subcutaneous injection of recombinant NGF (to mimic stress) resulted in an increased percentage of SP ؉ neurons in dorsal root ganglia, as measured by retrograde tracing. Taken together, these data suggest that NGF is a central element in the perifollicular neurogenic inflammation that develops during the murine skin response to stress and antagonizing NGF may be a promising therapeutic approach to counter the negative effect of stress on hair growth. Recently, we have introduced a mouse model launching experimental evidence that stress-induced hair loss is fact, and not fiction, as every so often imputed by a number of dermatologists. This mouse model provides new insights into the pathophysiology of stress-induced hair growth inhibition and permits exploration of various strategies for therapeutic intervention. 1,2 In this model, exposure to sonic stress inhibits the growth of a hair shaft producing (anagen) hair follicle by premature induction of hair follicle regression (catagen) and up-regulated keratinocyte apoptosis. At the same time, it induces neurogenic inflammation characterized by perifollicular mast cell degranulation and accumulation of antigen-presenting cells, eg, activated macrophages. 3 The neuropeptide substance P (SP) was identified as a key mediator of stress-induced hair growth inhibition, since increased number of SP-immunreactive nerve fibers were present in the skin of stressed mice and hair growth inhibition could be blocked by SP-receptor antagonists.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

Peters

Handjiski

Kuhlmei

et al. 2004

The American Journal of Pathology

Self Cite

114

161

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“…Neurotrophin catagen induction is absent in p75 null skin or when p75 is antagonized (Lindner et al 1997;Botchkarev et al 1999aBotchkarev et al ,2000Botchkarev et al ,2003. In our study, catagen is induced in late anagen skin by treatment with 7S NGF containing ' Figure 4 Immunohistochemical localization of nerve growth factor (NGF), TrkA, proNGF, and p75 in the murine anagen hair follicle.…”

Section: Discussionmentioning

confidence: 49%

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

Peters

Hendrix

Gölz

et al. 2006

J Histochem Cytochem.

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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.

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“…Nerve growth factor (NGF) is synthesized and released by human keratinocytes and also by epidermal fibroblasts (Pincelli and Marconi, 2000;Micera et al, 2001). Based on the previous study that both the p75 NTR and the high-affinity NGF receptor (trk) are involved in catagen-anagen control of hair follicle keratinocytes (Botchkarev et al, 2000), it is possible that p75 NTR are also involved in cell fate control for epithelial keratinocyte stem cells through cell-cell interactions including epithelial-mesenchymal interactions.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin receptor p75NTR characterizes human esophageal keratinocyte stem cells in vitro

et al. 2003

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We report here that human esophageal keratinocyte stem cells are characterized by the expression of the lowaffinity neurotrophin receptor p75 NTR and differentially expressed cell adhesion molecules, the b1 and b4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the p75 NTR -positive cell subset is immature relative to the other predominant subpopulations coexpressing b1 integrin at higher levels. The p75 NTR -positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and selfamplification of the p75 NTR -positive cell subset. These findings strongly implicate p75 NTR as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.

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A role for p75 neurotrophin receptor in the control of apoptosis‐driven hair follicle regression

Cited by 97 publications

References 67 publications

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

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

Neurotrophin receptor p75NTR characterizes human esophageal keratinocyte stem cells in vitro

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