- Email: [email protected]
Wnt Signaling: It Gets More Humorous with Age
Dispatch R923
substantially more patient than other animals. Given the surprising outcome of the comparison between chimpanzees and people, Rosati et al. [8] were compelled to rule out other possible explanations for the results. For example, one might argue that people really just didn’t care about the food reward and instead favored the instantaneous option to minimize the time spent in the experiment: however, the experimenters told the subjects that the experiment would take 45 minutes no matter what choices they made and all subjects were equally motivated as measured by the time taken to reach for the food. Alternatively, subjects may have simply been attempting to maximize their short-term reward rate [9]. To counter this proposal, the authors performed a careful analysis that took into account food handling times and time between trials to show that such a strategy would lead to much greater impulsivity than was observed. A final possibility is that the human subjects who participated in this study were just plain more impulsive than people studied in previous reports. To address this issue, Rosati et al. [8] ran a control experiment in which humans chose between immediate and delayed monetary rewards. They found that people were much more patient when the rewards
were money than when they were food. These results clearly show that temporal discounting depends strongly on reward type [5,10,11] and throw into question the generality of findings using a single experimental paradigm. These results provide compelling evidence that some animals can be remarkably patient and that humans can be remarkably impulsive when waiting for food rewards. Moreover, these observations suggest that self-control may not be uniquely human and may have evolved in primates sometime before the divergence of humans and other apes some five to eight million years ago. More generally, these results suggest that patience itself is not a single biological trait, like running speed — nor is it a virtue. The capacity for self-control may instead be viewed as a cognitive adaptation that evolves in response to selective pressures favoring delayed gratification and may be differentially deployed in distinct behavioral contexts. References 1. Rachlin, H. (2000). The Science of Self-Control (Cambridge, MA: Harvard University Press). 2. Tattersall, I., Delson, E., and Van Couvering, J. (1988). Encyclopedia of Human Evolution and Prehistory (New York: Garland Publishing Co). 3. Frederick, S., Loewenstein, G., and O’Donoghue, T. (2002). Time discounting and time preference: a critical review. J. Econom. Lit. 40, 351–401.
Wnt Signaling: It Gets More Humorous with Age In addition to its myriad of contributions in development, disease and regeneration, recent research implicates the Wnt/b-catenin signaling cascade in yet another biological process — aging. The latest role of Wnt uncovers new complexities and opportunities for modulating the Wnt/b-catenin pathway in regenerative medicine. Bryan D. White1,2, Nghi K. Nguyen1,3 and Randall T. Moon1,* Decreased stem cell function and a decline in tissue regeneration are hallmarks of aging. Although stem cell dysfunction may not
4. Green, L., and Myerson, J. (2004). A discounting framework for choice with delayed and probabilistic rewards. Psychol. Bull. 130, 769–792. 5. Hayden, B.Y., Parikh, P.C., Deaner, R.O., and Platt, M.L. (2007). Economic principles motivating social attention in humans. Proc. R. Soc. Lond. B 274, 1751–1756. 6. Mazur, J.E. (1987). An adjusting procedure for studying delayed reinforcement. In Quantitative Analyses of Behavior, vol. 5. The Effect of Delay and Intervening Events on Reinforcement Value, M.L. Commons, J.E. Mazur, J.A. Nevin, and H. Rachlin, eds. (Mahway, NJ: Erlbaum). 7. Stevens, J.R., Hallinan, E.V., and Hauser, M.D. (2005). The ecology and evolution of patience in two New World monkeys. Biol. Lett. 1, 223–226. 8. Rosati, A., Stevens, J., Hare, B., and Hauser, M. (2007). The evolutionary origins of human patience: temporal preferences in chimpanzees, bonobos, and human adults. Curr. Biol. 17, 1663–1668. 9. Stephens, D.W., and Krebs, J.R. (1986). Foraging Theory (Princeton, NJ: Princeton University Press). 10. Bickel, W.K., and Marsch, L.A. (2001). Toward a behavioral economic understanding of drug dependence: delay discounting processes. Addiction 96, 73–86. 11. McClure, S.M., Ericson, K.M., Laibson, D.I., Loewenstein, G., and Cohen, J.D. (2007). Time discounting for primary rewards. J. Neurosci. 27, 5796–5804. 12. Hayden, B.Y., and Platt, M.L. (2007). Temporal discounting predicts risk sensitivity in rhesus macaques. Curr. Biol. 17, 49–53.
cause aging, it may underlie the diminished regenerative response in aged animals [1]. Whether such stem cell dysfunction is caused by intrinsic changes in aged stem cells, changes in the extracellular environment, or both, is being debated. Two recent papers by
Department of Neurobiology, Center for Neuroeconomic Studies, and Center for Cognitive Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2007.08.061
Brack et al. [2] and Liu et al. [3] show that, surprisingly, Wnt activity is increased in aged serum and in a mouse model of accelerated aging. This increased Wnt signaling may contribute to stem cell dysfunction in aged animals. Increased Wnt/b-catenin Signaling in Aged Mice In order to study age-dependent changes in stem cell number and function, Liu et al. [3] utilized klotho knock out mice, which exhibit many age-related disorders as a result of accelerated aging [4]. Klotho is a transmembrane protein expressed in the kidney and
Current Biology Vol 17 No 21 R924
question whether there might be age-related effects of long-term lithium treatment, which is known to activate the ß-catenin pathway.
A
+Dkk Time
Time
Time
+Wnt
?
Senescence Senescence Senescence B
Young serum
Aged serum WA
WA
WA
WA
Aged serum + Dkk WA
WA
WA
WA WA
Injury
Injury
Regeneration WA
Wnt activity
WA
Fibrosis
WA
WA
Injury Regeneration
Muscle and satellite cell Current Biology
Figure 1. Modulating the Wnt/ß-catenin pathway in aging. (A) While the recent study by Liu et al. [3] showed that increased Wnt signaling accelerates senescence, the question remains whether a Wnt inhibitor such as Dickkopf can delay cellular aging. (B) Inhibiting the increased Wnt activity in aged serum restores the regenerative response of stem cells.
choroid plexus and its extracellular domain is secreted into the blood, enabling it to act as an anti-aging hormone [5]. Liu et al. [3] found that various stem cell populations were altered in the klotho mice and looked to see if Klotho might functionally interact with a known soluble modulator of stem cells such as Wnt. Using in vitro cell assays, the authors found that Klotho binds to Wnt and reduces its ability to activate b-catenin. Experiments using a b-catenin reporter mouse showed that Wnt/b-catenin signaling is upregulated in the hair follicle in klotho knock out mice and that addition of Klotho inhibits this b-catenin signaling. Finally, Liu et al. [3] showed that continuous Wnt exposure causes senescence in both in vitro and in vivo settings, highlighting the differential response of signal activation based on its duration. There are a number of exciting questions that surface based on
the work of Liu et al. [3]. First and most importantly, can inhibition of Wnt/b-catenin signaling slow aging? Inhibition of Wnt/b-catenin signaling might not slow aging, but it might slow senescence of some stem cell populations; however, the question remains whether inhibition of Wnt signaling could slow normal age-related senescence of stem cells (Figure 1A). Even if one could reduce senescence in stem cell populations, one needs to consider the importance of senescence and the ramifications of its inhibition. According to recent research, even quiescent hematopoietic stem cells acquire DNA damage during aging [6]. Inhibiting senescence may, therefore, result in a stem cell pool that is accumulating DNA damage and is thus unable to functionally respond to injury, and instead is poised for mutagenic transformation. Finally, the finding that continuous Wnt exposure causes senescence raises the
Modulating Wnt Signaling to Increase Regeneration In the second study, Brack et al. [2] also discovered increased Wnt activity in aged tissues when they studied muscle regeneration in young and old mice. In vivo studies from the Rando lab [7] had previously shown that muscle regeneration is improved and that fibrosis is diminished when old muscle is exposed to a youthful systemic environment after injury. However, it had remained unclear if specific differences in serum between old and young animals underlie the change in regenerative capacity. Using a b-catenin reporter gene to detect Wnt signaling in mouse muscle progenitors, Brack et al. [2] now found that signaling through b-catenin increases with age. In addition, an increase in b-catenin signaling upon application of aged serum could be abolished by the addition of a specific Wnt-signaling inhibitor. Most strikingly, they found that injection of the inhibitor directly into muscle could decrease the fibrotic response of aged muscle (Figure 1B). These exciting findings challenge the current dogma in the field, which states that Wnts act in a short-range manner, spanning two to three cell diameters from the secreting cell [8]. The results of Brack et al. [2] clearly show that a component of serum can bind Wnt receptors and can activate ßcatenin signaling in an endocrine fashion. If the signaling activity is really due to a Wnt ligand, the question arises of what is biochemically different about this soluble Wnt that enables it to travel in serum? How does long-range Wnt signaling interact with and modulate local paracrine Wnt signaling? Are there other shortrange signaling factors that might act in an endocrine fashion? Although Brack et al. [2] discovered that Wnt or Wnt-like molecules are present in the serum, it is still unknown what causes the difference in Wnt activity with age. In aged animals, an upregulation of
Dispatch R925
Wnt ligand could cause an increase in signaling or alternatively a downregulation of Wnt inhibitor could be responsible for the change. Given the findings of Liu et al. [3], could an age-related decrease of Klotho protein levels in serum be responsible for the increase in Wnt activity with age? As there are several other secreted Wnt inhibitors — including Dickkopfs, secreted Frizzled-related proteins, and even Wnts that work through a ß-catenin-independent pathway — are any or all of them involved in aging? Where is the source of Wnt or the inhibitors? Most significantly, could systemic application of a Wnt inhibitor improve the response of aged muscle progenitors after injury? Taken together, the works of Brack et al. [2] and Liu et al. [3] suggest that inhibiting Wnt/ b-catenin signaling might improve stem cell function in the regenerative responses of aged tissues. This finding contrasts with studies suggesting that increased Wnt/b-catenin signaling may increase regeneration of hair [9] and bone [10] of younger mice. There is ample precedence in the literature for a Wnt signal having different effects on a given cell population and its descendents depending on when the Wnt signal is received. For example, during
zebrafish heart development, an early Wnt signal promotes cardiomyocyte formation, while a few hours later the same signal inhibits formation of these cells [11]. Given that Wnt/b-catenin signaling has various effects on a multitude of stem cell populations, one has to be careful when manipulating this pathway, now that it has become clear that it is involved not only in development, disease, and regeneration, but also in aging processes. Although Wnt signaling gets more humorous with age, we might be the ones left laughing if inhibiting them slows aging and increases the regenerative potential of various stem cells. 1. Rando, T.A. (2006). Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086. 2. Brack, A.S., Conboy, M.J., Roy, S., Lee, M., Kuo, C.J., Keller, C., and Rando, T.A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810. 3. Liu, H., Fergusson, M.M., Castilho, R.M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I.I., Schimel, D., Kuo, C.J., et al. (2007). Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806. 4. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51. 5. Kurosu, H., Yamamoto, M., Clark, J.D., Pastor, J.V., Nandi, A., Gurnani, P., McGuinness, O.P., Chikuda, H.,
In the cooperatively breeding superb fairy-wren, helpers have negligible effect on breeding success. So why help? The answer is hidden in the size of the eggs.
Raising chicks to adulthood puts a huge demand on breeding birds. In a survey of the sustainable metabolic rates of 37 species, only two examples were found of animals that could work at more than seven times their resting metabolic rate: breeding birds and cyclists on the Tour de France [1].
7.
8. 9.
10.
11.
References
Behavioural Ecology: Hidden Benefits Revealed
Ashleigh Griffin
6.
In cooperatively breeding species, parents can share this load with helpers, usually birds from previous breeding attempts that have remained on the natal territory [2–4]. Unsurprisingly, parent birds benefit from the presence of helpers with greater numbers of young successfully raised to adulthood on average [5]. There are, however, some
Yamaguchi, M., Kawaguchi, H., et al. (2005). Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833. Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., and Weissman, I.L. (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729. Conboy, I.M., Conboy, M.J., Wagers, A.J., Girma, E.R., Weissman, I.L., and Rando, T.A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764. Miller, J.R. (2002). The Wnts. Genome Biol. 3, REVIEWS3001. Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S.E., and Cotsarelis, G. (2007). Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320. Kim, J.B., Leucht, P., Lam, K., Luppen, C., Ten Berge, D., Nusse, R., and Helms, J.A. (2007). Bone regeneration is regulated by Wnt signaling. J. Bone. Miner. Res., epub ahead of print. Ueno, S., Weidinger, G., Osugi, T., Kohn, A.D., Golob, J.L., Pabon, L., Reinecke, H., Moon, R.T., and Murry, C.E. (2007). Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc. Natl. Acad. Sci. USA 104, 9685–9690.
1Howard
Hughes Medical Institute, Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine. 2Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, Washington 98195, USA. 3Department of Biological Sciences, Stanford University, Stanford California 94305, USA. *E-mail: [email protected] DOI: 10.1016/j.cub.2007.08.062
intriguing exceptions. In the superb fairy-wren Malurus cyaneus (Figure 1), helpers have no effect on the survival or mass of chicks [6]. This immediately raises the question: why are superb fairy-wren helpers helping? (Why would Lance Armstrong sit at the bottom of the Pyrenees on a cycling machine?) A convincing answer to this question has recently been provided by Russell et al. [7]. This study shows that broods with helpers start off at a disadvantage, with smaller eggs and correspondingly smaller hatchlings relative to broods reared by pairs only. More specifically, the presence of helpers was
substantially more patient than other animals. Given the surprising outcome of the comparison between chimpanzees and people, Rosati et al. [8] were compelled to rule out other possible explanations for the results. For example, one might argue that people really just didn’t care about the food reward and instead favored the instantaneous option to minimize the time spent in the experiment: however, the experimenters told the subjects that the experiment would take 45 minutes no matter what choices they made and all subjects were equally motivated as measured by the time taken to reach for the food. Alternatively, subjects may have simply been attempting to maximize their short-term reward rate [9]. To counter this proposal, the authors performed a careful analysis that took into account food handling times and time between trials to show that such a strategy would lead to much greater impulsivity than was observed. A final possibility is that the human subjects who participated in this study were just plain more impulsive than people studied in previous reports. To address this issue, Rosati et al. [8] ran a control experiment in which humans chose between immediate and delayed monetary rewards. They found that people were much more patient when the rewards
were money than when they were food. These results clearly show that temporal discounting depends strongly on reward type [5,10,11] and throw into question the generality of findings using a single experimental paradigm. These results provide compelling evidence that some animals can be remarkably patient and that humans can be remarkably impulsive when waiting for food rewards. Moreover, these observations suggest that self-control may not be uniquely human and may have evolved in primates sometime before the divergence of humans and other apes some five to eight million years ago. More generally, these results suggest that patience itself is not a single biological trait, like running speed — nor is it a virtue. The capacity for self-control may instead be viewed as a cognitive adaptation that evolves in response to selective pressures favoring delayed gratification and may be differentially deployed in distinct behavioral contexts. References 1. Rachlin, H. (2000). The Science of Self-Control (Cambridge, MA: Harvard University Press). 2. Tattersall, I., Delson, E., and Van Couvering, J. (1988). Encyclopedia of Human Evolution and Prehistory (New York: Garland Publishing Co). 3. Frederick, S., Loewenstein, G., and O’Donoghue, T. (2002). Time discounting and time preference: a critical review. J. Econom. Lit. 40, 351–401.
Wnt Signaling: It Gets More Humorous with Age In addition to its myriad of contributions in development, disease and regeneration, recent research implicates the Wnt/b-catenin signaling cascade in yet another biological process — aging. The latest role of Wnt uncovers new complexities and opportunities for modulating the Wnt/b-catenin pathway in regenerative medicine. Bryan D. White1,2, Nghi K. Nguyen1,3 and Randall T. Moon1,* Decreased stem cell function and a decline in tissue regeneration are hallmarks of aging. Although stem cell dysfunction may not
4. Green, L., and Myerson, J. (2004). A discounting framework for choice with delayed and probabilistic rewards. Psychol. Bull. 130, 769–792. 5. Hayden, B.Y., Parikh, P.C., Deaner, R.O., and Platt, M.L. (2007). Economic principles motivating social attention in humans. Proc. R. Soc. Lond. B 274, 1751–1756. 6. Mazur, J.E. (1987). An adjusting procedure for studying delayed reinforcement. In Quantitative Analyses of Behavior, vol. 5. The Effect of Delay and Intervening Events on Reinforcement Value, M.L. Commons, J.E. Mazur, J.A. Nevin, and H. Rachlin, eds. (Mahway, NJ: Erlbaum). 7. Stevens, J.R., Hallinan, E.V., and Hauser, M.D. (2005). The ecology and evolution of patience in two New World monkeys. Biol. Lett. 1, 223–226. 8. Rosati, A., Stevens, J., Hare, B., and Hauser, M. (2007). The evolutionary origins of human patience: temporal preferences in chimpanzees, bonobos, and human adults. Curr. Biol. 17, 1663–1668. 9. Stephens, D.W., and Krebs, J.R. (1986). Foraging Theory (Princeton, NJ: Princeton University Press). 10. Bickel, W.K., and Marsch, L.A. (2001). Toward a behavioral economic understanding of drug dependence: delay discounting processes. Addiction 96, 73–86. 11. McClure, S.M., Ericson, K.M., Laibson, D.I., Loewenstein, G., and Cohen, J.D. (2007). Time discounting for primary rewards. J. Neurosci. 27, 5796–5804. 12. Hayden, B.Y., and Platt, M.L. (2007). Temporal discounting predicts risk sensitivity in rhesus macaques. Curr. Biol. 17, 49–53.
cause aging, it may underlie the diminished regenerative response in aged animals [1]. Whether such stem cell dysfunction is caused by intrinsic changes in aged stem cells, changes in the extracellular environment, or both, is being debated. Two recent papers by
Department of Neurobiology, Center for Neuroeconomic Studies, and Center for Cognitive Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2007.08.061
Brack et al. [2] and Liu et al. [3] show that, surprisingly, Wnt activity is increased in aged serum and in a mouse model of accelerated aging. This increased Wnt signaling may contribute to stem cell dysfunction in aged animals. Increased Wnt/b-catenin Signaling in Aged Mice In order to study age-dependent changes in stem cell number and function, Liu et al. [3] utilized klotho knock out mice, which exhibit many age-related disorders as a result of accelerated aging [4]. Klotho is a transmembrane protein expressed in the kidney and
Current Biology Vol 17 No 21 R924
question whether there might be age-related effects of long-term lithium treatment, which is known to activate the ß-catenin pathway.
A
+Dkk Time
Time
Time
+Wnt
?
Senescence Senescence Senescence B
Young serum
Aged serum WA
WA
WA
WA
Aged serum + Dkk WA
WA
WA
WA WA
Injury
Injury
Regeneration WA
Wnt activity
WA
Fibrosis
WA
WA
Injury Regeneration
Muscle and satellite cell Current Biology
Figure 1. Modulating the Wnt/ß-catenin pathway in aging. (A) While the recent study by Liu et al. [3] showed that increased Wnt signaling accelerates senescence, the question remains whether a Wnt inhibitor such as Dickkopf can delay cellular aging. (B) Inhibiting the increased Wnt activity in aged serum restores the regenerative response of stem cells.
choroid plexus and its extracellular domain is secreted into the blood, enabling it to act as an anti-aging hormone [5]. Liu et al. [3] found that various stem cell populations were altered in the klotho mice and looked to see if Klotho might functionally interact with a known soluble modulator of stem cells such as Wnt. Using in vitro cell assays, the authors found that Klotho binds to Wnt and reduces its ability to activate b-catenin. Experiments using a b-catenin reporter mouse showed that Wnt/b-catenin signaling is upregulated in the hair follicle in klotho knock out mice and that addition of Klotho inhibits this b-catenin signaling. Finally, Liu et al. [3] showed that continuous Wnt exposure causes senescence in both in vitro and in vivo settings, highlighting the differential response of signal activation based on its duration. There are a number of exciting questions that surface based on
the work of Liu et al. [3]. First and most importantly, can inhibition of Wnt/b-catenin signaling slow aging? Inhibition of Wnt/b-catenin signaling might not slow aging, but it might slow senescence of some stem cell populations; however, the question remains whether inhibition of Wnt signaling could slow normal age-related senescence of stem cells (Figure 1A). Even if one could reduce senescence in stem cell populations, one needs to consider the importance of senescence and the ramifications of its inhibition. According to recent research, even quiescent hematopoietic stem cells acquire DNA damage during aging [6]. Inhibiting senescence may, therefore, result in a stem cell pool that is accumulating DNA damage and is thus unable to functionally respond to injury, and instead is poised for mutagenic transformation. Finally, the finding that continuous Wnt exposure causes senescence raises the
Modulating Wnt Signaling to Increase Regeneration In the second study, Brack et al. [2] also discovered increased Wnt activity in aged tissues when they studied muscle regeneration in young and old mice. In vivo studies from the Rando lab [7] had previously shown that muscle regeneration is improved and that fibrosis is diminished when old muscle is exposed to a youthful systemic environment after injury. However, it had remained unclear if specific differences in serum between old and young animals underlie the change in regenerative capacity. Using a b-catenin reporter gene to detect Wnt signaling in mouse muscle progenitors, Brack et al. [2] now found that signaling through b-catenin increases with age. In addition, an increase in b-catenin signaling upon application of aged serum could be abolished by the addition of a specific Wnt-signaling inhibitor. Most strikingly, they found that injection of the inhibitor directly into muscle could decrease the fibrotic response of aged muscle (Figure 1B). These exciting findings challenge the current dogma in the field, which states that Wnts act in a short-range manner, spanning two to three cell diameters from the secreting cell [8]. The results of Brack et al. [2] clearly show that a component of serum can bind Wnt receptors and can activate ßcatenin signaling in an endocrine fashion. If the signaling activity is really due to a Wnt ligand, the question arises of what is biochemically different about this soluble Wnt that enables it to travel in serum? How does long-range Wnt signaling interact with and modulate local paracrine Wnt signaling? Are there other shortrange signaling factors that might act in an endocrine fashion? Although Brack et al. [2] discovered that Wnt or Wnt-like molecules are present in the serum, it is still unknown what causes the difference in Wnt activity with age. In aged animals, an upregulation of
Dispatch R925
Wnt ligand could cause an increase in signaling or alternatively a downregulation of Wnt inhibitor could be responsible for the change. Given the findings of Liu et al. [3], could an age-related decrease of Klotho protein levels in serum be responsible for the increase in Wnt activity with age? As there are several other secreted Wnt inhibitors — including Dickkopfs, secreted Frizzled-related proteins, and even Wnts that work through a ß-catenin-independent pathway — are any or all of them involved in aging? Where is the source of Wnt or the inhibitors? Most significantly, could systemic application of a Wnt inhibitor improve the response of aged muscle progenitors after injury? Taken together, the works of Brack et al. [2] and Liu et al. [3] suggest that inhibiting Wnt/ b-catenin signaling might improve stem cell function in the regenerative responses of aged tissues. This finding contrasts with studies suggesting that increased Wnt/b-catenin signaling may increase regeneration of hair [9] and bone [10] of younger mice. There is ample precedence in the literature for a Wnt signal having different effects on a given cell population and its descendents depending on when the Wnt signal is received. For example, during
zebrafish heart development, an early Wnt signal promotes cardiomyocyte formation, while a few hours later the same signal inhibits formation of these cells [11]. Given that Wnt/b-catenin signaling has various effects on a multitude of stem cell populations, one has to be careful when manipulating this pathway, now that it has become clear that it is involved not only in development, disease, and regeneration, but also in aging processes. Although Wnt signaling gets more humorous with age, we might be the ones left laughing if inhibiting them slows aging and increases the regenerative potential of various stem cells. 1. Rando, T.A. (2006). Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086. 2. Brack, A.S., Conboy, M.J., Roy, S., Lee, M., Kuo, C.J., Keller, C., and Rando, T.A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810. 3. Liu, H., Fergusson, M.M., Castilho, R.M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I.I., Schimel, D., Kuo, C.J., et al. (2007). Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806. 4. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51. 5. Kurosu, H., Yamamoto, M., Clark, J.D., Pastor, J.V., Nandi, A., Gurnani, P., McGuinness, O.P., Chikuda, H.,
In the cooperatively breeding superb fairy-wren, helpers have negligible effect on breeding success. So why help? The answer is hidden in the size of the eggs.
Raising chicks to adulthood puts a huge demand on breeding birds. In a survey of the sustainable metabolic rates of 37 species, only two examples were found of animals that could work at more than seven times their resting metabolic rate: breeding birds and cyclists on the Tour de France [1].
7.
8. 9.
10.
11.
References
Behavioural Ecology: Hidden Benefits Revealed
Ashleigh Griffin
6.
In cooperatively breeding species, parents can share this load with helpers, usually birds from previous breeding attempts that have remained on the natal territory [2–4]. Unsurprisingly, parent birds benefit from the presence of helpers with greater numbers of young successfully raised to adulthood on average [5]. There are, however, some
Yamaguchi, M., Kawaguchi, H., et al. (2005). Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833. Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., and Weissman, I.L. (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729. Conboy, I.M., Conboy, M.J., Wagers, A.J., Girma, E.R., Weissman, I.L., and Rando, T.A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764. Miller, J.R. (2002). The Wnts. Genome Biol. 3, REVIEWS3001. Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S.E., and Cotsarelis, G. (2007). Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320. Kim, J.B., Leucht, P., Lam, K., Luppen, C., Ten Berge, D., Nusse, R., and Helms, J.A. (2007). Bone regeneration is regulated by Wnt signaling. J. Bone. Miner. Res., epub ahead of print. Ueno, S., Weidinger, G., Osugi, T., Kohn, A.D., Golob, J.L., Pabon, L., Reinecke, H., Moon, R.T., and Murry, C.E. (2007). Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc. Natl. Acad. Sci. USA 104, 9685–9690.
1Howard
Hughes Medical Institute, Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine. 2Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, Washington 98195, USA. 3Department of Biological Sciences, Stanford University, Stanford California 94305, USA. *E-mail: [email protected] DOI: 10.1016/j.cub.2007.08.062
intriguing exceptions. In the superb fairy-wren Malurus cyaneus (Figure 1), helpers have no effect on the survival or mass of chicks [6]. This immediately raises the question: why are superb fairy-wren helpers helping? (Why would Lance Armstrong sit at the bottom of the Pyrenees on a cycling machine?) A convincing answer to this question has recently been provided by Russell et al. [7]. This study shows that broods with helpers start off at a disadvantage, with smaller eggs and correspondingly smaller hatchlings relative to broods reared by pairs only. More specifically, the presence of helpers was