DOI: 10.1111/exd.12244
Commentary
www.wileyonlinelibrary.com/journal/EXD
Commentary on: Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis Yuval Ramot1 and Leah A. Vardy2,3 1 Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2A*STAR Institute of Medical Biology, Singapore, Singapore; 3School of Biological Sciences, Nanyang Technological University, Singapore, Singapore Correspondence: Leah A. Vardy, A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos, 138648 Singapore, Tel.: +65 64070174, Fax: +65 64642048, e-mail: [email protected]; Yuval Ramot, Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Tel.: +972 267111, Fax: +972 6777299, e-mail: [email protected]
Abstract: Polyamines are cationic amines essential for cellular proliferation. Recently, their role in hair follicle (HF) growth has started to be explored, but their exact function is still obscure. In the October issue of Experimental Dermatology, Luke et al. follow the observation that putrescine overproducing mice and hairless (HR) mutant mice show a similar clinical phenotype of hair loss and dermal cyst formation. They show that HR and putrescine form a negative regulatory feedback mechanism, which might regulate hair cycling and therefore control hair growth. This study
Polyamines have long been known to be important for proliferative cells, but recently, their role in hair growth has begun to be examined. Polyamine levels are tightly regulated by synthesis, uptake, export and degradation. Their synthesis is regulated largely by ornithine decarboxylase (ODC1) and adenosylmethionine decarboxylase, and their degradation by spermidine/spermine N1acetyltransferase (SSAT) (Fig. 1). Despite their importance for a wide array of cellular processes, very few molecular targets of the polyamines have been defined. This was the case in the hair follicle (HF). Polyamines are important for hair growth and cycling, but little is known about their exact functions. ODC1 levels are
AdoMet
Ornithine
AMD1 dcAdoMet
ODC1
SPDS
Putrescine SSAT
SPMS
Spermidine SSAT Spermine
Figure 1. Simplified scheme of the polyamine metabolic pathways. Degradation pathways are represented by red arrows and synthesis pathways by blue arrows. AdoMet, S-adenosylmethionine; AMD1, adenosylmethionine decarboxylase; dcAdoMet, decarboxylated adenosylmethionine; ODC1, ornithine decarboxylase; SPDS, spermidine synthase; SPMS, spermine synthase; SSAT, spermidine/spermine N1-acetyltransferase.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 697–698
clearly demonstrates that a strong connection exists between HR and polyamines although there are probably additional molecular pathways involved in the polyamine regulation of hair growth which remain to be discovered. Key words: hair follicle – hair loss – hairless – polyamines – putrescine
Accepted for publication 16 September 2013
increased in the epithelium of anagen HFs but are dramatically reduced in catagen (1,2). Interestingly, upregulation of SSAT or ODC1 leads to hair loss and dermal cysts in mouse models (3,4). This counter-intuitive observation can be explained by the elevated putrescine levels in both situations. It was proposed that continuous putrescine expression promotes proliferation and eliminates differentiation resulting in over proliferation of outer root sheath keratinocytes and dermal cyst formation (5,6). While overexpression of ODC1 and high putrescine levels are linked to hair loss, inhibition of putrescine synthesis by the potent ODC1 inhibitor DFMO has a similar effect, possibly due to enhanced anagen to catagen transition (7). Many other studies have demonstrated the effect of altered polyamine levels on HF cycling (8). These studies demonstrate the essential role played by putrescine in hair growth and highlight the importance of regulated changes in ODC1 levels during the hair cycle. While the link between polyamines and hair growth is strong, their molecular targets have remained unclear. The recent study by Luke et al. sheds light on how putrescine may regulate the hair cycle (9). They have investigated the observation that the ODC1 overexpression phenotype was very similar to the hairless (Hr) mutant phenotype (4). Mutations in Hr result in a failure of hair cycling and regrowth, leading to congenital hair loss, thus firmly establishing it as an essential regulator of hair growth (10). Luke et al. demonstrate that there is a negative regulatory loop between ODC1 and HR. In normal human keratinocytes (NHKs), overexpression of HR leads to reduced ODC1 levels, partly by increasing expression of the MYC antagonists MXI1 and MXD3, and mutations in Hr result in increased ODC1 levels. This study is further extended by observing that ODC1 overexpression in NHKs decreases Hr levels. Decreased Hr levels were also observed in the epidermis from SSAT overexpressing mice. Both these situations
697
Commentary
result in increased putrescine levels suggesting that putrescine itself can repress Hr levels. These observations link polyamine levels to the well-established hair cycle regulator, HR, and the authors infer from this that the polyamines likely function in a similar manner in the HF given the dramatic hair phenotypes in the HR and ODC1 overexpressing mutant mice. Luke et al. observe that the SSAT overexpressing and Hr mutant mice have similar but distinct hair loss phenotypes. SSAT overexpressing mice display a patchy loss of hair due to inadequately anchored club hairs which are dislodged on mechanical stimulation, while the Hr mutants show a more organized and active loss of hair. It is likely that in addition to HR, additional targets for putrescine are present which are responsible for these differences. This study describes microarrays from putrescine treated keratinocytes that identify a number of potential putrescine targets that could play a role in hair cycling. It is of interest that patients with Marie Unna hereditary hypotrichosis show a different pattern of hair loss than atrichia with popular lesions (APL) patients although both conditions are caused by perturbations in HR expression. While Marie Unna patients present with patchy hair loss which progresses to an androgenetic alopecia-like pattern (11), APL patients quickly progress to complete hair loss in childhood (12). Therefore, similar to the mice phenotypes, mutations in the HR protein in humans do not necessarily lead to the same hair phenotype. ODC1 expression is high during anagen and decreased upon catagen induction (2). HR protein shows a reciprocal expression pattern and is high in catagen and telogen but decreased in anagen (13). Evidence presented in this study suggests that fluctuating HR levels regulate ODC1 mRNA transcription. Additionally, modulation of intracellular putrescine levels through ODC1 or SSAT overexpression can in turn repress Hr levels. While Hr mRNA is believed to be expressed throughout the HF cycle, the levels of putrescine that promote its repression are likely above what would be seen in a normal cycling HF. It has been proposed that fluctuations in ODC1 may be regulated by local mediators in the HF that promote its levels in anagen. During catagen, these mediators decline and ODC1 levels drop (6,8). The study by Luke et al. suggests that HR is this mediator but instead of activating ODC1, it represses its levels in catagen when present at high levels. In anagen when HR protein levels drop, ODC1 accumulates resulting in increased putrescine
References
1 Nancarrow M J, Nesci A, Hynd P I et al. Mech Dev 1999: 84: 161–164. 2 Pi L, Ji J, Oh Y et al. Int J Trichol 2009: 1: 65 Poster abtsract P18. 3 Janne J, Alhonen L, Pietila M et al. Eur J Biochem 2004: 271: 877–894. 4 Panteleyev A A, Christiano A M, O’Brien T G et al. Exp Dermatol 2000: 9: 146–151. 5 Pietila M, Parkkinen J J, Alhonen L et al. J Invest Dermatol 2001: 116: 801–805. 6 Soler A P, Gilliard G, Megosh L C et al. J Invest Dermatol 1996: 106: 1108–1113.
698
Anagen
Telogen
Catagen
Telogen
HR Hr
Hr
Hr
Odc1
Odc1
Odc1
Putrescine
Putrescine
Putrescine
ODC1 Figure 2. Reciprocal regulation of HR and ODC1 during the hair cycle.
levels, allowing anagen progression (Fig. 2). When putrescine levels get too high as in SSAT overexpression, a feedback loop inhibits HR resulting in a hair loss phenotype. While putrescine levels are important for HR expression, it should be remembered that the polyamines spermine and spermidine are also controlled by ODC1 (Fig. 1). Particularly important is spermidine, which has been shown to induce anagen and enhance hair shaft elongation (14). The exact mechanism by which spermidine exerts these effects is still unknown, but the current study shows that DFMO, which also inhibits spermidine production, decreased Hr expression. Therefore, it is possible that spermidine may also lead to changes in HR expression. This emphasizes the importance of fine tuning polyamine levels in the HF, as changes in any of the polyamines can lead to severe hair phenotypes. The regulation governing hair growth is complex, and many different interacting pathways are involved (15). The polyamines, which clearly have an essential role in the HF, have many different targets and can function in a cell-type-specific manner. Recent advances in HF culturing systems will greatly help to delineate the networks controlling the HF cycle and distinguish between HF and epidermal-specific functions. This study takes a step closer to deciphering these controls and reveals an interesting connection between polyamines and HR which has important implications for HF regulation. Further understanding of this connection will greatly aid in the understanding and potentially treatment of a variety of different hair disorders.
Author contribution Yuval Ramot and Leah Vardy wrote the manuscript.
Conflict of interest The authors have declared no conflict of interests.
7 Kloepper J E, Sugawara K, Al-Nuaimi Y et al. Exp Dermatol 2010: 19: 305–312. 8 Ramot Y, Pietila M, Giuliani G et al. Exp Dermatol 2010: 19: 784–790. 9 Luke C T, Casta A, Kim H et al. Exp Dermatol 2013: 22: 644–649. 10 Thompson C C. Nucl Recept Signal 2009: 7: e010. 11 Ramot Y, Horev L, Smolovich I et al. Exp Dermatol 2010: 19: e320–e322. 12 Zlotogorski A, Hochberg Z, Mirmirani P et al. Arch Dermatol 2003: 139: 1591–1596.
13 Beaudoin G M 3rd, Sisk J M, Coulombe P A et al. Proc Natl Acad Sci U S A 2005: 102: 14 653–14 658. 14 Ramot Y, Tiede S, Biro T et al. PLoS ONE 2011: 6: e22564. 15 Betz R C, Cabral R M, Christiano A M et al. J Invest Dermatol 2012: 132: 906–914.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 697–698
Commentary
www.wileyonlinelibrary.com/journal/EXD
Commentary on: Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis Yuval Ramot1 and Leah A. Vardy2,3 1 Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2A*STAR Institute of Medical Biology, Singapore, Singapore; 3School of Biological Sciences, Nanyang Technological University, Singapore, Singapore Correspondence: Leah A. Vardy, A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos, 138648 Singapore, Tel.: +65 64070174, Fax: +65 64642048, e-mail: [email protected]; Yuval Ramot, Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Tel.: +972 267111, Fax: +972 6777299, e-mail: [email protected]
Abstract: Polyamines are cationic amines essential for cellular proliferation. Recently, their role in hair follicle (HF) growth has started to be explored, but their exact function is still obscure. In the October issue of Experimental Dermatology, Luke et al. follow the observation that putrescine overproducing mice and hairless (HR) mutant mice show a similar clinical phenotype of hair loss and dermal cyst formation. They show that HR and putrescine form a negative regulatory feedback mechanism, which might regulate hair cycling and therefore control hair growth. This study
Polyamines have long been known to be important for proliferative cells, but recently, their role in hair growth has begun to be examined. Polyamine levels are tightly regulated by synthesis, uptake, export and degradation. Their synthesis is regulated largely by ornithine decarboxylase (ODC1) and adenosylmethionine decarboxylase, and their degradation by spermidine/spermine N1acetyltransferase (SSAT) (Fig. 1). Despite their importance for a wide array of cellular processes, very few molecular targets of the polyamines have been defined. This was the case in the hair follicle (HF). Polyamines are important for hair growth and cycling, but little is known about their exact functions. ODC1 levels are
AdoMet
Ornithine
AMD1 dcAdoMet
ODC1
SPDS
Putrescine SSAT
SPMS
Spermidine SSAT Spermine
Figure 1. Simplified scheme of the polyamine metabolic pathways. Degradation pathways are represented by red arrows and synthesis pathways by blue arrows. AdoMet, S-adenosylmethionine; AMD1, adenosylmethionine decarboxylase; dcAdoMet, decarboxylated adenosylmethionine; ODC1, ornithine decarboxylase; SPDS, spermidine synthase; SPMS, spermine synthase; SSAT, spermidine/spermine N1-acetyltransferase.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 697–698
clearly demonstrates that a strong connection exists between HR and polyamines although there are probably additional molecular pathways involved in the polyamine regulation of hair growth which remain to be discovered. Key words: hair follicle – hair loss – hairless – polyamines – putrescine
Accepted for publication 16 September 2013
increased in the epithelium of anagen HFs but are dramatically reduced in catagen (1,2). Interestingly, upregulation of SSAT or ODC1 leads to hair loss and dermal cysts in mouse models (3,4). This counter-intuitive observation can be explained by the elevated putrescine levels in both situations. It was proposed that continuous putrescine expression promotes proliferation and eliminates differentiation resulting in over proliferation of outer root sheath keratinocytes and dermal cyst formation (5,6). While overexpression of ODC1 and high putrescine levels are linked to hair loss, inhibition of putrescine synthesis by the potent ODC1 inhibitor DFMO has a similar effect, possibly due to enhanced anagen to catagen transition (7). Many other studies have demonstrated the effect of altered polyamine levels on HF cycling (8). These studies demonstrate the essential role played by putrescine in hair growth and highlight the importance of regulated changes in ODC1 levels during the hair cycle. While the link between polyamines and hair growth is strong, their molecular targets have remained unclear. The recent study by Luke et al. sheds light on how putrescine may regulate the hair cycle (9). They have investigated the observation that the ODC1 overexpression phenotype was very similar to the hairless (Hr) mutant phenotype (4). Mutations in Hr result in a failure of hair cycling and regrowth, leading to congenital hair loss, thus firmly establishing it as an essential regulator of hair growth (10). Luke et al. demonstrate that there is a negative regulatory loop between ODC1 and HR. In normal human keratinocytes (NHKs), overexpression of HR leads to reduced ODC1 levels, partly by increasing expression of the MYC antagonists MXI1 and MXD3, and mutations in Hr result in increased ODC1 levels. This study is further extended by observing that ODC1 overexpression in NHKs decreases Hr levels. Decreased Hr levels were also observed in the epidermis from SSAT overexpressing mice. Both these situations
697
Commentary
result in increased putrescine levels suggesting that putrescine itself can repress Hr levels. These observations link polyamine levels to the well-established hair cycle regulator, HR, and the authors infer from this that the polyamines likely function in a similar manner in the HF given the dramatic hair phenotypes in the HR and ODC1 overexpressing mutant mice. Luke et al. observe that the SSAT overexpressing and Hr mutant mice have similar but distinct hair loss phenotypes. SSAT overexpressing mice display a patchy loss of hair due to inadequately anchored club hairs which are dislodged on mechanical stimulation, while the Hr mutants show a more organized and active loss of hair. It is likely that in addition to HR, additional targets for putrescine are present which are responsible for these differences. This study describes microarrays from putrescine treated keratinocytes that identify a number of potential putrescine targets that could play a role in hair cycling. It is of interest that patients with Marie Unna hereditary hypotrichosis show a different pattern of hair loss than atrichia with popular lesions (APL) patients although both conditions are caused by perturbations in HR expression. While Marie Unna patients present with patchy hair loss which progresses to an androgenetic alopecia-like pattern (11), APL patients quickly progress to complete hair loss in childhood (12). Therefore, similar to the mice phenotypes, mutations in the HR protein in humans do not necessarily lead to the same hair phenotype. ODC1 expression is high during anagen and decreased upon catagen induction (2). HR protein shows a reciprocal expression pattern and is high in catagen and telogen but decreased in anagen (13). Evidence presented in this study suggests that fluctuating HR levels regulate ODC1 mRNA transcription. Additionally, modulation of intracellular putrescine levels through ODC1 or SSAT overexpression can in turn repress Hr levels. While Hr mRNA is believed to be expressed throughout the HF cycle, the levels of putrescine that promote its repression are likely above what would be seen in a normal cycling HF. It has been proposed that fluctuations in ODC1 may be regulated by local mediators in the HF that promote its levels in anagen. During catagen, these mediators decline and ODC1 levels drop (6,8). The study by Luke et al. suggests that HR is this mediator but instead of activating ODC1, it represses its levels in catagen when present at high levels. In anagen when HR protein levels drop, ODC1 accumulates resulting in increased putrescine
References
1 Nancarrow M J, Nesci A, Hynd P I et al. Mech Dev 1999: 84: 161–164. 2 Pi L, Ji J, Oh Y et al. Int J Trichol 2009: 1: 65 Poster abtsract P18. 3 Janne J, Alhonen L, Pietila M et al. Eur J Biochem 2004: 271: 877–894. 4 Panteleyev A A, Christiano A M, O’Brien T G et al. Exp Dermatol 2000: 9: 146–151. 5 Pietila M, Parkkinen J J, Alhonen L et al. J Invest Dermatol 2001: 116: 801–805. 6 Soler A P, Gilliard G, Megosh L C et al. J Invest Dermatol 1996: 106: 1108–1113.
698
Anagen
Telogen
Catagen
Telogen
HR Hr
Hr
Hr
Odc1
Odc1
Odc1
Putrescine
Putrescine
Putrescine
ODC1 Figure 2. Reciprocal regulation of HR and ODC1 during the hair cycle.
levels, allowing anagen progression (Fig. 2). When putrescine levels get too high as in SSAT overexpression, a feedback loop inhibits HR resulting in a hair loss phenotype. While putrescine levels are important for HR expression, it should be remembered that the polyamines spermine and spermidine are also controlled by ODC1 (Fig. 1). Particularly important is spermidine, which has been shown to induce anagen and enhance hair shaft elongation (14). The exact mechanism by which spermidine exerts these effects is still unknown, but the current study shows that DFMO, which also inhibits spermidine production, decreased Hr expression. Therefore, it is possible that spermidine may also lead to changes in HR expression. This emphasizes the importance of fine tuning polyamine levels in the HF, as changes in any of the polyamines can lead to severe hair phenotypes. The regulation governing hair growth is complex, and many different interacting pathways are involved (15). The polyamines, which clearly have an essential role in the HF, have many different targets and can function in a cell-type-specific manner. Recent advances in HF culturing systems will greatly help to delineate the networks controlling the HF cycle and distinguish between HF and epidermal-specific functions. This study takes a step closer to deciphering these controls and reveals an interesting connection between polyamines and HR which has important implications for HF regulation. Further understanding of this connection will greatly aid in the understanding and potentially treatment of a variety of different hair disorders.
Author contribution Yuval Ramot and Leah Vardy wrote the manuscript.
Conflict of interest The authors have declared no conflict of interests.
7 Kloepper J E, Sugawara K, Al-Nuaimi Y et al. Exp Dermatol 2010: 19: 305–312. 8 Ramot Y, Pietila M, Giuliani G et al. Exp Dermatol 2010: 19: 784–790. 9 Luke C T, Casta A, Kim H et al. Exp Dermatol 2013: 22: 644–649. 10 Thompson C C. Nucl Recept Signal 2009: 7: e010. 11 Ramot Y, Horev L, Smolovich I et al. Exp Dermatol 2010: 19: e320–e322. 12 Zlotogorski A, Hochberg Z, Mirmirani P et al. Arch Dermatol 2003: 139: 1591–1596.
13 Beaudoin G M 3rd, Sisk J M, Coulombe P A et al. Proc Natl Acad Sci U S A 2005: 102: 14 653–14 658. 14 Ramot Y, Tiede S, Biro T et al. PLoS ONE 2011: 6: e22564. 15 Betz R C, Cabral R M, Christiano A M et al. J Invest Dermatol 2012: 132: 906–914.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 22, 697–698
