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Second, its E3-ubiquitin ligase activity is essen-tial to initiate, at least in part, a series of interme-diate steps that ultimately lead to degradation of IκB and, hence, nuclear translocation of NF-κB7,8. Thus, Birc2 stimulates cellular survival in vitro.

Vascular functionThe findings by Santoro et al. advance our knowledge of Birc2 by defining, for the first time, a role for Birc2 in vivo. Loss-of-function studies in mice have been complicated by the fact that mammals have two homologs, Birc2 and Birc3 (also known as IAP2). Mice lacking either Birc2 or Birc3 are healthy and viable, presumably because these proteins have redun-dant activities and compensate for each other’s loss9,10. Only when challenged by inflammatory stimuli do cells from these animals undergo apoptosis. Because double-deficient mice have not yet been generated, the in vivo role of these genes has remained enigmatic. Zebrafish, by contrast, have only a single Birc2 gene.

Using an unbiased forward-genetics approach in zebrafish, Santoro et al. identi-fied a mutant that they termed tomato (tom) because of its red appearance, a phenotype caused by bleeding from abnormally formed blood vessels2. Through positional cloning experiments, the authors found that the tom phenotype resulted from a loss-of-function mutation in Birc2, which they confirmed by knockdown of Birc2 gene expression in wild-type embryos. Through further analysis of the mutant, the authors showed that blood vessels first form normally but then disinte-grate because of endothelial cell apoptosis, indicating that Birc2 is required for vessel maintenance and endothelial survival.

Why does loss of Birc2 cause an endo-thelial cell–specific defect? This is surpris-ing, because in mice, Birc2 and Birc3 are expressed in many cell types, and endothe-lial cells express other IAPs, such as survivin and XIAP. Among all IAPs, loss of function of Birc2 in zebrafish causes the most vascu-lar-specific phenotype. This is likely to be related to its restricted pattern of expression in zebrafish endothelial cells. As embryonic development relies on a functional vascula-ture, the survival of blood vessels is of utmost importance and, hence, proper survival sig-nals must protect endothelial cells against cell death. Obviously, the findings by Santoro et al. do not exclude the possibility that Birc2 might also regulate the survival of other cell types at later developmental stages.

The findings by Santoro et al. also raise a number of outstanding questions. For instance, endothelial cells in the adult are quiescent; does Birc2 also mediate the sur-vival of these cells? Also, is Birc2 active in growing vessels in tumors or other diseases? Does Birc2 act downstream of TNFR2 or other death receptors, such as Fas and CD40, which also regulate angiogenesis11,12? TNF stimulates but also inhibits endothelial cell survival; is this dual activity related to Birc2? Finally, expression of survivin is strongly upregulated by VEGF; does Birc2 act inde-pendently of VEGF, one of the prime survival signals for endothelial cells?

The study by Santoro et al. may also have implications for future design of antian-giogenic therapy. Available antiangiogenic agents (all VEGF inhibitors) induce endo-thelial cell apoptosis in existing vessels. However, many cancer patients are refrac-

tory or become resistant to VEGF-inhibitor therapy1. Hence, additional antiangiogenic agents with complementary mechanisms are required. It will thus be important to assess whether Birc2 acts independently of the survival pathway mediated by VEGF. If the survival mechanisms of Birc2 and VEGF are unrelated, inhibiting Birc2 might be an attractive strategy to enhance the antian-giogenic efficacy of VEGF inhibitors, and it might even be useful in cancer patients who have become resistant to VEGF inhibitor therapy. Because Birc2 has enzymatic activ-ity, it might become an attractive target for drug development. The fundamental insights obtained by Santoro et al. through a series of elegant genetic studies in fish not only open new research avenues but might also offer attractive opportunities for translational medicine.

1. Carmeliet, P. Nature 438, 932–936 (2005).2. Santoro, M.M., Samuel, T., Mitchell, T., Reed, J.C. &

Stainier, D.Y. Nat. Genet. 39, 1397–1402 (2007).3. Salvesen, G.S. & Duckett, C.S. Nat. Rev. Mol. Cell

Biol. 3, 401–410 (2002).4. Vaux, D.L. & Silke, J. Nat. Rev. Mol. Cell Biol. 6,

287–297 (2005).5. Micheau, O. & Tschopp, J. Cell 114, 181–190

(2003).6. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K. &

Tschopp, J. Mol. Cell. Biol. 21, 5299–5305 (2001).7. Samuel, T. et al. J. Biol. Chem. 281, 1080–1090

(2006).8. Tang, E.D., Wang, C.Y., Xiong, Y. & Guan, K.L. J. Biol.

Chem. 278, 37297–37305 (2003).9. Conze, D.B. et al. Mol. Cell. Biol. 25, 3348–3356

(2005).10. Conte, D. et al. Mol. Cell. Biol. 26, 699–708

(2006).11. Aoudjit, F. & Vuori, K. J. Cell Biol. 152, 633–643

(2001).12. Reinders, M.E., Sho, M., Robertson, S.W., Geehan,

C.S. & Briscoe, D.M. J. Immunol. 171, 1534–1541 (2003).

Red sky in the morning, shepherd’s warningVinod Kumar & Philip A Wigge

A new study provides insight into the way plants integrate information from the environment to anticipate the onset of winter. Plants are able to combine information about light quality and ambient temperature to activate the cold- acclimation pathway.

Vinod Kumar and Philip A. Wigge are in the Department of Cell and Developmental Biology, John Innes Centre, Norwich NR4 7UH, UK. e-mail: philip.wigge@bbsrc.ac.uk

climates. Although plants are largely unable to modulate their core temperature, they are far from passive participants, deploying an impres-sive range of signaling pathways to sense change in temperature and adjust many aspects of their growth and development accordingly1,2. Forewarned is forearmed, and recent work is revealing a fascinating degree of complexity by which plants sense, and attempt to anticipate,

changes in temperature during the seasons and the day-night cycle. On page 1410 of this issue, Franklin and Whitelam3 add a valuable piece to the jigsaw, showing that information from two key pathways in environmental sensing—light quality and ambient temperature—are inte-grated to enable the expression of genes that confer resistance to freezing temperatures in Arabidopsis thaliana. The study shows that

Being rooted to the spot, plants are vulnerable to changes in their environments. Temperature in particular is quite challenging and can eas-ily fluctuate within a 40 °C range in temperate

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although either decreased ambient temperature or low light quality alone is unable to activate the cold-acclimation pathway, the combination of these two signals protects plants from freez-ing. The authors suggest that this may reflect an adaptive mechanism by which plants are able to sense the encroaching winter during autumn, when twilight increases (that is, the average light quality decreases) and the temperature starts to drop.

The cold light of autumnAlthough plants grown at ambient tempera-tures are rapidly killed when placed at subzero temperatures, pretreatment at 4 °C induces the expression of cold-protective genes by the CRT/DRE binding factor (CBF) pathway (Fig. 1), which is sufficient to allow the plant to survive subsequent chilling. This process of cold accli-mation has been known for a number of years, and mutants have been identified for several proteins in the pathway, particularly SFR6, that have key roles in enabling cold acclimation4,5. Indeed, overexpression of CBF genes is suffi-cient to confer freezing tolerance6. Previously, it was shown that CBF induction is gated by the circadian clock7. This new observation that CBF activity can be potentiated by the combination of a low ratio of red to far-red light and low ambient temperature provides an elegant mechanism by which the plant can sense impending winter during the lon-ger dusk and cooler autumn temperatures. Remarkably, the combination of treatment at 16 °C and low light is able to confer freezing tolerance on A. thaliana seedlings.

Light quality is perceived by photoreceptors, or phytochromes, that are sensitive to the red/far-red ratio. Environmental conditions, such as plant crowding, lower this ratio, causing the phytochromes to be inactivated and leading to greater plant growth (the shade-avoidance response). This study proves a crucial link between light quality and cold acclimation. Consistently, the authors are able to mimic the effect of poor light quality genetically, as phyD mutants grown at 16 °C are also cold accli-mated. This temperature-responsive pathway again puts the phytochromes in a central posi-tion in modulating developmental responses. Previous work in the Whitelam laboratory has shown that light-quality sensed by the phyto-chromes has a key role in inducing the floral integrator FT8. Intriguingly, FT is also a key component that is very sensitive to ambient temperature9,10, and higher ambient tempera-tures lead to significantly greater FT induction and early flowering.

A plant’s perceptionsLike many key studies, this one raises almost as many interesting questions as it answers. Particularly, what is the mechanism by which phytochromes modulate the expression of particular genes such as FT and CBF genes in a temperature-dependent fashion? Some exciting clues are suggested by the gene PFT1, which has a role in linking phytochrome signaling to FT expression11. The recent description of PFT1 as part of the plant mediator complex may shed some light on this question12.

The use of coinciding signals to modulate plant development was proposed theoretically by Bünning more than 70 years ago13. Previous examples of this phenomenon in plant biology include the induction of flowering by photope-riod14 as well as rhythmical growth rate15. The work of Franklin and Whitelam3 would suggest an additional example of the coincidence of both low ambient temperature and light qual-ity in activating cold acclimation, which is itself gated by the circadian clock. It will be fascinat-ing in the next few years to start to examine the underlying mechanisms by which temperature is perceived in plants and the way these complex pathways are integrated. Although reductionist studies of individual components under con-trolled conditions have enabled extraordinary

progress, we are only just beginning to under-stand how a plant growing under natural condi-tions, with multiple stresses and demands on its resources, optimizes its seed set. This study is an exciting harbinger of a new era of understand-ing regarding how plants grow and thrive in a dynamic and complex environment.

1. Heggie, L. & Halliday, K.J. Int. J. Dev. Biol. 49, 675–687 (2005).

2. Samach, A. & Wigge, P.A. Curr. Opin. Plant Biol. 8, 483–486 (2005).

3. Franklin, K.A. & Whitelam, G.C. Nat. Genet. 39, 1410–1413 (2007).

4. Warren, G., McKown, R., Marin, A.L. & Teutonico, R. Plant Physiol. 111, 1011–1019 (1996).

5. Boyce, J.M. et al. Plant J. 34, 395–406 (2003).6. Jaglo-Ottosen, K.R., Gilmour, S.J., Zarka, D.G.,

Schabenberger, O. & Thomashow, M.F. Science 280, 104–106 (1998).

7. Fowler, S.G., Cook, D. & Thomashow, M.F. Plant Physiol. 137, 961–968 (2005).

8. Halliday, K.J., Salter, M.G., Thingnaes, E. & Whitelam, G.C. Plant J. 33, 875–885 (2003).

9. Blazquez, M.A., Ahn, J.H. & Weigel, D. Nat. Genet. 33, 168–171 (2003).

10. Balasubramanian, S., Sureshkumar, S., Lempe, J. & Weigel, D. PLoS Genet. 2, e106 (2006).

11. Cerdan, P.D. & Chory, J. Nature 423, 881–885 (2003).

12. Backstrom, S., Elfving, N., Nilsson, R., Wingsle, G. & Bjorklund, S. Mol. Cell 26, 717–729 (2007).

13. Bünning, E. Ber. Dtsch. Bot. Ges. 54, 590–607 (1936).

14. Mouradov, A., Cremer, F. & Coupland, G. Plant Cell 14 Suppl, S111–S130 (2002).

15. Nozue, K. et al. Nature 448, 358–361 (2007).

CBF

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Figure 1 Phytochromes have a central role in coordinating responses to both light quality and the pathway that senses ambient temperature. Although cold adaptation is usually activated by the CBF pathway only at temperatures around 0 °C, the combination of poor light quality (decreased ratio of red to far-red light) as sensed by phytochromes and moderately low ambient temperature (16 °C) is sufficient to trigger cold adaptation. Notably, other adaptive changes in plant development, such as flowering, are also influenced by ambient temperature in a phytochrome-modulated fashion, in this case through the expression of the floral-inducing gene FT. These processes are also gated by the circadian clock.

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