17β-Estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-α pathway

Chanda, Sanjay; Robinette, Carole; Couse, John F.; Smart, Robert C.

doi:10.1152/ajpendo.2000.278.2.e202

Cited by 73 publications

(66 citation statements)

References 41 publications

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“…It is worth noting that antagonism of estrogen receptor signaling by the compound ICI-182780 has been shown to promote anagen onset in mice (Oh and Smart 1996). However, our data are consistent with a subsequent study (Chanda et al 2000), which demonstrated that topical treatment with 4-OHT has no significant effect on progression to anagen.…”

Section: Chronic Activation Of ␤-Catenin Function In Follicular Epithsupporting

confidence: 90%

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Mater¹,

Kolligs²,

Dlugosz³

et al. 2003

Genes Dev.

241

190

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Wnts have key roles in many developmental processes, including hair follicle growth and differentiation. Stabilization of ␤-catenin is essential in the canonical Wnt signaling pathway. We developed transgenic mice expressing a regulated form of ␤-catenin in the skin. Chronic activation of ␤-catenin in resting (telogen) hair follicles resulted in changes consistent with induction of an exaggerated, aberrant growth phase (anagen). Transient activation of ␤-catenin produced a normal anagen. Our data lend strong support to the notion that a Wnt/ ␤-catenin signal operating on hair follicle precursor cells serves as a crucial proximal signal for the telogen-anagen transition. Wnt family proteins function in short-range signaling. They regulate cell fate, adhesion, differentiation, proliferation, and motility, and many studies have demonstrated their critical roles in development (for review, see Peifer and Polakis 2000). Mutational defects in Wnt signaling have a major contributing role in a broad spectrum of cancers (Polakis 2000). At present, it appears many Wnts exert their effects, at least in part, through a "canonical" signaling pathway in which stabilization of the ␤-catenin protein is essential. Much of the ␤-catenin protein in the cell is associated with the cell membrane, where ␤-catenin binds to and links E-cadherin to the cytoskeleton through ␤-catenin's binding to ␣-catenin. A fraction of the ␤-catenin is free in the cytoplasm and/or nucleus. Normally, in the absence of Wnt signals, ␤-catenin is bound and negatively regulated by a protein complex that includes the adenomatous polyposis coli (APC) and axin tumor suppressor proteins as well as glycogen synthase kinase-3␤ (GSK-3␤; for review, see Peifer and Polakis 2000). This complex promotes phosphorylation of ␤-catenin at a number of N-terminal serine and threonine residues, and the phosphorylated ␤-catenin is ubiquitinated and subsequently degraded by the proteasome.Binding of Wnts to their cognate frizzled and low-density lipoprotein receptor-related protein receptor complexes on the cell surface leads to inhibition of GSK-3␤ activity and increased levels of free ␤-catenin in the cell (Peifer and Polakis 2000). In cancers, inactivating mutations in the APC or axin proteins or activating mutations affecting N-terminal phosphorylation sites in ␤-catenin lead to stabilization of ␤-catenin (Polakis 2000). Regardless of whether Wnt signals or mutational defects stabilize ␤-catenin, following its accumulation in the cell, ␤-catenin can complex in the nucleus with T cell factor/ lymphoid enhancer factor (TCF/LEF) transcription regulators, leading to activation of TCF-regulated genes (a list of candidate TCF target genes is provided at: http:// www.stanford.edu/∼rnusse/wntwindow.html).Wnt/␤-catenin signaling has been proposed to function in hair follicle morphogenesis and differentiation (Kishimoto et al. 2000;Fuchs et al. 2001;Millar 2002). Hair follicle morphogenesis is characterized by the downward growth of epithelial hair follicle precursor cells into the ...

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Section: Chronic Activation Of ␤-Catenin Function In Follicular Epithsupporting

confidence: 90%

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Mater¹,

Kolligs²,

Dlugosz³

et al. 2003

Genes Dev.

241

190

View full text Add to dashboard Cite

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“…Interestingly, a similar inhibitory effect of estrogens has been documented previously in the case of self-renewing transit-amplifying progenitors that give rise to cells of the inner root sheath and the mature hair fiber (14,44). Decreased CFU-OB self-renewal could result from a direct action of estrogens on this progenitor or indirectly via the regulation of one or more factors produced by other cell(s) in the bone marrow.…”

Section: Discussionsupporting

confidence: 69%

Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17β-estradiol

Gregorio¹,

Yamamoto²,

Ali³

et al. 2001

J. Clin. Invest.

121

105

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“…It has been reported that ER␣ was expressed only in the dermal papilla and outer root sheath of telogen and early anagen mouse hair follicles and that ER␤ was undetectable (26,250). Recently, however, we could show that both ER␣ and ER␤ as well as the splice variant ER␤ ins are expressed throughout the entire, depilation-induced murine hair cycle at both the protein and RNA levels (28).…”

Section: B Estrogen Receptor Expression In the Hair Folliclementioning

confidence: 65%

“…Together with the fact that E2 modifies androgen metabolism and vice versa (250,251) and the intriguing cross talk examples discussed above, this already renders the number of potential signaling cross talks and cross-modulation events that may impact how E2 can alter the growth of a given hair follicle in a defined gender and location daunting. This gets even more complicated if one enters additional recent findings into the equation.…”

Section: H Other Potentially Important Signaling Cross Talks With Inmentioning

confidence: 99%

The Hair Follicle as an Estrogen Target and Source

et al. 2006

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For many decades, androgens have dominated endocrine research in hair growth control. Androgen metabolism and the androgen receptor currently are the key targets for systemic, pharmacological hair growth control in clinical medicine. However, it has long been known that estrogens also profoundly alter hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). Besides altering the transcription of genes with estrogen-responsive elements, 17␤-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target.Here, we chart the recent renaissance of estrogen research in hair research; explain why the hair follicle offers an ideal, clinically relevant test system for studying the role of sex steroids, their receptors, and interactions in neuroectodermal-mesodermal interaction systems in general; and illustrate how it can be exploited to identify novel functions and signaling cross talks of ER-mediated signaling. Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia. While defining major open questions, unsolved clinical challenges, and particularly promising research avenues in this area, we argue that the time has come to pay estrogen-mediated signaling the full attention it deserves in future endocrinological therapy of common hair growth disorders. (Endocrine Reviews 27: 677-706, 2006)

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17β-Estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-α pathway

Abstract: Estradiol (E(2)) applied topically twice weekly to mouse skin at doses as low as 1 nmol inhibited hair growth by blocking the transition of the hair follicle from the resting phase (telogen) to the growth phase (anagen). In contrast, application of Show more

Cited by 73 publications

References 41 publications

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17β-estradiol

The Hair Follicle as an Estrogen Target and Source

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