Alopecia (hair loss) Hedgehog articles

Posted: Mon Jan 30, 2006 1:21 pm

Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
J Invest Dermatol. 2005 Oct;125(4):638-46.
Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL.

Curis Inc., Cambridge, Massachusetts, USA. rpaladini@curis.com

The hedgehog (Hh) family of intercellular signaling proteins is intricately linked to the development and patterning of almost every major vertebrate organ system. In the skin, sonic hedgehog (Shh) is required for hair follicle morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. We recently described the identification and characterization of synthetic, non-peptidyl small molecule agonists of the Hh pathway. In this study, we examined the ability of a topically applied Hh-agonist to modulate follicular cycling in adult mouse skin. We report that the Hh-agonist can stimulate the transition from the resting (telogen) to the growth (anagen) stage of the hair cycle in adult mouse skin. Hh-agonist-induced hair growth caused no detectable differences in epidermal proliferation, differentiation, or in the endogenous Hh-signaling pathway as measured by Gli1, Shh, Ptc1, and Gli2 gene expression when compared with a normal hair cycle. In addition, we demonstrate that Hh-agonist is active in human scalp in vitro as measured by Gli1 gene expression. These results suggest that the topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant follicular cycling in the scalp including androgenetic alopecia (pattern hair loss).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16185261&query_hl=10&itool=pubmed_docsum
beta-Catenin and Hedgehog Signal Strength Can Specify Number and Location of Hair Follicles in Adult Epidermis without Recruitment of Bulge Stem Cells.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15992546&query_hl=1
Dev Cell. 2005 Jul;9(1):121-31.

Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells.

Silva-Vargas V, Lo Celso C, Giangreco A, Ofstad T, Prowse DM, Braun KM, Watt FM.

Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

Using K14deltaNbeta-cateninER transgenic mice, we show that short-term, low-level beta-catenin activation stimulates de novo hair follicle formation from sebaceous glands and interfollicular epidermis, while only sustained, high-level activation induces new follicles from preexisting follicles. The Hedgehog pathway is upregulated by beta-catenin activation, and inhibition of Hedgehog signaling converts the low beta-catenin phenotype to wild-type epidermis and the high phenotype to low. beta-catenin-induced follicles contain clonogenic keratinocytes that express bulge markers; the follicles induce dermal papillae and provide a niche for melanocytes, and they undergo 4OHT-dependent cycles of growth and regression. New follicles induced in interfollicular epidermis are derived from that cellular compartment and not through bulge stem cell migration or division. These results demonstrate the remarkable capacity of adult epidermis to be reprogrammed by titrating beta-catenin and Hedgehog signal strength and establish that cells from interfollicular epidermis can acquire certain characteristics of bulge stem cells.
Controls of hair follicle cycling
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11152763&query_hl=1
Physiol Rev. 2001 Jan;81(1):449-494. Related Articles, Links

Controls of hair follicle cycling.

Stenn KS, Paus R.

Beauty Genome Sciences Inc., Skillman, New Jersey, USA. kstenn@cpcus.jnj.com

Nearly 50 years ago, Chase published a review of hair cycling in which he detailed hair growth in the mouse and integrated hair biology with the biology of his day. In this review we have used Chase as our model and tried to put the adult hair follicle growth cycle in perspective. We have tried to sketch the adult hair follicle cycle, as we know it today and what needs to be known. Above all, we hope that this work will serve as an introduction to basic biologists who are looking for a defined biological system that illustrates many of the challenges of modern biology: cell differentiation, epithelial-mesenchymal interactions, stem cell biology, pattern formation, apoptosis, cell and organ growth cycles, and pigmentation. The most important theme in studying the cycling hair follicle is that the follicle is a regenerating system. By traversing the phases of the cycle (growth, regression, resting, shedding, then growth again), the follicle demonstrates the unusual ability to completely regenerate itself. The basis for this regeneration rests in the unique follicular epithelial and mesenchymal components and their interactions. Recently, some of the molecular signals making up these interactions have been defined. They involve gene families also found in other regenerating systems such as fibroblast growth factor, transforming growth factor-beta, Wnt pathway, Sonic hedgehog, neurotrophins, and homeobox. For the immediate future, our challenge is to define the molecular basis for hair follicle growth control, to regenerate a mature hair follicle in vitro from defined populations, and to offer real solutions to our patients' problems.
De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9845363&query_hl=1
Cell. 1998 Nov 25;95(5):605-14. Related Articles, Links

De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin.

Gat U, DasGupta R, Degenstein L, Fuchs E.

Howard Hughes Medical Institute, The University of Chicago, Illinois 60637, USA.

An effector of intercellular adhesion, beta-catenin also functions in Wnt signaling, associating with Lef-1/Tcf DNA-binding proteins to form a transcription factor. We report that this pathway operates in keratinocytes and that mice expressing a stabilized beta-catenin controlled by an epidermal promoter undergo a process resembling de novo hair morphogenesis. The new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis. As in embryologically initiated hair germs, transgenic follicles induce Lef-1, but follicles are disoriented and defective in sonic hedgehog polarization. Additionally, proliferation continues unchecked, resulting in two types of tumors also found in humans. Our findings suggest that transient beta-catenin stabilization may be a key player in the long-sought epidermal signal leading to hair development and implicate aberrant beta-catenin activation in hair tumors.
Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11752010&query_hl=1
J Natl Cancer Inst. 2001 Dec 19;93(24):1858-64. Related Articles, Links

Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia.

Sato N, Leopold PL, Crystal RG.

Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.

BACKGROUND: The Sonic hedgehog (Shh) gene is involved in the initiation of hair growth. We have shown that localized, transient, enhanced expression of the Shh gene in mouse skin mediated by an adenovirus (AdShh) vector accelerates initiation of the anagen (i.e., growth) phase of hair follicle development. Because hair regrowth in chemotherapy-induced alopecia is associated with follicle cell proliferation and active melanogenesis similar to that observed in the anagen phase of normal hair growth, we examined whether AdShh-mediated Shh expression would accelerate hair regrowth in the skin of mice with chemotherapy-induced alopecia. METHODS: After establishment of cyclophosphamide-induced alopecia, in either 3- or 7-week-old mice, AdShh or a control vector (AdNull) was delivered to dorsal skin by intradermal injection. Hair regrowth and melanogenesis were assessed by histology and gross morphology. Fisher's exact test was used to compare differences in outcomes between AdShh-treated and control (AdNull-treated or not injected with any vector [naive]) mice. All statistical tests were two-sided. RESULTS: Northern blot analysis confirmed enhanced Shh expression after AdShh administration in 7-week-old mice. Two weeks after AdShh administration, the injection site (all of five mice) showed large, anagen-phase hair follicles with a normal distribution of melanin. In contrast, both skin treated with AdNull (all of five mice) and skin from naive mice (all of five mice) showed dystrophic hair follicles with irregular distribution of melanin (P<.001 in both comparisons). Gross morphologic observations confirmed that AdShh-treated mice, but not naive mice or AdNull-treated mice, showed skin darkening at the injection site indicative of entry into anagen phase (P<.001 in both comparisons). AdShh treatment of 3-week-old mice with cyclophosphamide-induced alopecia was followed by accelerated hair follicle recovery (19 of 22 mice); such recovery was not observed at this rate in AdNull-treated or naive skin (P<.001 for both comparisons). CONCLUSION: Localized, transient, enhanced expression of Shh gene in skin, mediated by an adenovirus vector, might be a future strategy to accelerate hair follicle regrowth after chemotherapy-induced alopecia.
Hair cycle regulation of Hedgehog signal reception
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12648487&query_hl=1
Dev Biol. 2003 Mar 15;255(2):238-48. Related Articles, Links

Hair cycle regulation of Hedgehog signal reception.

Oro AE, Higgins K.

Program in Epithelial Biology, CCSR 2145c, 269 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305, USA. oro@cmgm.stanford.edu

Proper patterning of self-renewing organs, like the hair follicle, requires exquisite regulation of growth signals. Sonic hedgehog (Shh) signaling in skin controls the growth and morphogenesis of hair follicle epithelium in part through regulating the Gli transcription factors. While ectopic induction of Shh target genes leads to hair follicle tumors, such as basal cell carcinomas, how Shh signaling normally functions during the cyclic process of hair development is unknown. Here, we show that, during the hair cycle, Shh expression and the ability of skin cells to respond to Shh signaling is spatially and temporally regulated. Induction of Shh target genes normally occurs only in the anagen hair follicle in response to expression of Shh. However, in patched1 heterozygous mice, putative tumor precursors form with concomitant induction of Shh target gene transcription only during anagen in follicular and interfollicular keratinocytes. Ectopic production of Gli1 accumulates Gli protein and induces Shh target genes and epithelial tumors at anagen but not other stages, pointing to a restricted competence occurring at the level of Gli protein accumulation. Delivery and reception of growth signals among multipotent cells are restricted in time and space to facilitate cyclic pattern formation.
Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10510326&query_hl=1
J Clin Invest. 1999 Oct;104(7):855-64. Related Articles, Links

Comment in:
J Clin Invest. 1999 Oct;104(7):851-3.

Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog.

Sato N, Leopold PL, Crystal RG.

Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University-New York Presbyterian Hospital, New York, New York 10021, USA.

Hair follicles form in prenatal skin and mature in the postnatal period, establishing a growth cycle in 3 phases: telogen (resting), anagen (growth), and catagen (regression). Based on the knowledge that Sonic hedgehog (Shh) expression is necessary for the embryonic development of hair follicles, and that anagen in the postnatal cycling follicle has morphologic similarities to the epithelial invagination process in embryonic skin, we hypothesized that localized, but transient, enhanced expression of the Shh gene in postnatal skin would accelerate initiation of anagen in the hair follicle cycle, with concomitant accelerated hair growth. To assess this concept, an E1(-) adenovirus vector, AdShh, was used to transfer the murine Shh cDNA to skin of postnatal day 19 C57BL/6 mice. The treated skin showed increased mRNA expression of Shh, Patched (the Shh receptor), and Gli1 (a transcription factor in the Shh pathway). In mice receiving AdShh, but not in controls, acceleration into anagen was evident, since hair follicle size and melanogenesis increased and the hair-specific keratin ghHb-1 and the melanin synthesis-related tyrosinase mRNAs accumulated. Finally, C57BL/6 mice showed marked acceleration of the onset of new hair growth in the region of AdShh administration to skin 2 weeks after treatment, but not in control vector-treated or untreated areas. After 6 months, AdShh-treated skin showed normal hair and normal skin morphology. Together, these observations are consistent with the concept that upregulation of Shh activity in postnatal skin functions as a biologic switch that induces resting hair follicles to enter anagen with consequent hair growth.
Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11532396&query_hl=8
Curr Opin Genet Dev. 2001 Oct;11(5):541-6. Related Articles, Links

Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling.

Callahan CA, Oro AE.

Program in Epithelial Biology, Stanford University, CCSR Building, Room 2145, 269 Campus Drive, Stanford, CA 94305-5168, USA.

Epithelial organs such as the vertebrate hair control periodic self-renewal by regulating the growth of progenitor cells. Recent studies implicate Sonic hedgehog target gene induction in the growth of multipotent hair follicle epithelium and the development of a variety of hair follicle tumors such as basal cell carcinomas. These studies suggest Sonic hedgehog signaling may regulate progenitor cells in other organs.

Publication Types:
Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12533516&query_hl=1
Genes Dev. 2003 Jan 15;17(2):282-94. Related Articles, Links

Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development.

Mill P, Mo R, Fu H, Grachtchouk M, Kim PC, Dlugosz AA, Hui CC.

Program in Developmental Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

Sonic hedgehog (Shh) signaling plays a critical role in hair follicle development and skin cancer, but how it controls these processes remains unclear. Of the three Gli transcription factors involved in transducing Shh signals in vertebrates, we demonstrate here that Gli2 is the key mediator of Shh responses in skin. Similar to Shh(-/-) mice, Gli2(-/-) mutants exhibit an arrest in hair follicle development with reduced cell proliferation and Shh-responsive gene expression, but grossly normal epidermal differentiation. By transgenic rescue experiments, we show that epidermal Gli2 function alone is sufficient to restore hair follicle development in Gli2(-/-) skin. Furthermore, only a constitutively active form of Gli2, but not wild-type Gli2, can activate Shh-responsive gene expression and promote cell proliferation in Shh(-/-) skin. These observations indicate that Shh-dependent Gli2 activator function in the epidermis is essential for hair follicle development. Our data also reveal that Gli2 mediates the mitogenic effects of Shh by transcriptional activation of cyclin D1 and cyclin D2 in the developing hair follicles. Together, our results suggest that Shh-dependent Gli2 activation plays a critical role in epithelial homeostasis by promoting proliferation through the transcriptional control of cell cycle regulators.

[*]The Hedgehog and the hair follicle: a growing relationship
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10510325&query_hl=1
: J Clin Invest. 1999 Oct;104(7):851-3. Related Articles, Links

Comment on:
J Clin Invest. 1999 Oct;104(7):855-64.

The Hedgehog and the hair follicle: a growing relationship.

Dlugosz A.

Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 3310 CCGC/Box 0932, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0932, USA. dlugosza@umich.edu

Publication Types:
Comment
Review

PMID: 10510325 [PubMed - indexed for MEDLINE]