development, the authors provide compel-ling in vitro data that these effects are medi-ated by the Notch transcriptional co-activator MAML1 and by the target gene Hes1. But pre-vious studies8,9 reported that perturbing Notch transcriptional effectors in mice did not lead to leukaemia during the observation period. Together, these data point to the potential existence of non-canonical Notch effectors in blood stem cells, but more work is needed to clarify these discrepancies.

Klinakis et al.2 extend their work to human leukaemias harbouring inactivating mutations in members of the Notch pathway. Remark-ably, they find six mutations in several genes encoding Notch-pathway members in five out of 42 samples from patients with chronic myelomonocytic leukaemia. In in vitro experi-ments, these mutations disrupted Notch signalling. Furthermore, the authors show that Notch mutations coexist with muta-tions in pathways previously described in this cancer (those involving the proteins RAS, JAK2 and TET2). This observation indicates cooperativity between Notch loss and per-turbations in other signalling pathways implicated in blood cancers, but it needs to be verified in larger collections of patients’ samples — work that should be accompanied by functional studies.

Although decreased Notch function has been shown10–12 to promote tumour develop-ment in specific mouse models, Klinakis and colleagues’ work is important because it impli-cates decreased Notch function in human cancer development. Moreover, this paper2 highlights the importance of using mouse models, because work on these animals not only sheds light on gene function in physio-logical processes, it also helps us to understand human cancer genetics and, potentially, allows the design of new treatments.

This study also underscores the compli-cated part played by cell-signalling pathways in human disease and the challenges that researchers face in predicting suitable thera-peutic targets. Although the Notch pathway is certainly a prime drug target in T-cell acute lymphoblastic leukaemias/lymphomas, the therapeutic window may be dictated by the effects of Notch-pathway inhibition on other cell types, such as myeloid progenitors, as described here. Further investigation of the intricacies of Notch signalling in unaffected and malignant tissues will help to determine the best approaches to manipulating this pathway for optimal therapeutic response. ■

Demetrios Kalaitzidis and Scott A. Armstrong are at Children’s Hospital Boston, and Dana Farber Cancer Institute, Division of Hematology/Oncology, Boston, Massachusetts 02115, USA. e-mails: demetrios.kalaitzidis@childrens.harvard.edu; scott.armstrong@childrens. harvard.edu

1. Aster, J. C., Blacklow, S. C. & Pear, W. S. J. Pathol. 223, 263–274 (2011).

2. Klinakis, A. et al. Nature 473, 230–233 (2011).

3. Kopan, R. & IIagan, M. X. G. Cell 137, 216–233 (2009).

4. Koch, U. & Radtke, F. Curr. Top. Dev. Biol. 92, 411–455 (2010).

5. De Strooper, B., Vassar, R. & Golde, T. Nature Rev. Neurol. 6, 99–107 (2010).

6. Demehri, S. et al. PLoS Biol. 6, e123 (2008). 7. Dumortier, A. et al. PLoS One 5, e9258 (2010). 8. Duncan, A. W. et al. Nature Immunol. 6, 314–322

(2005). 9. Maillard, I. et al. Cell Stem Cell 2, 356–366 (2008). 10. Demehri, S., Turkoz, A. & Kopan, R. Cancer Cell 16,

55–66 (2009). 11. Liu, Z. et al. J. Clin. Invest. 121, 800–808

(2011). 12. Hanlon, L. et al. Cancer Res. 70, 4280–4286 (2010).

A S T R O P H Y S I C S

Era of the compact diskSome of the strangest galaxies in the Universe just got stranger. It seems that many galaxies in the early Universe not only packed a huge number of stars into a very small volume, but were also rotating rapidly.

P I E T E R V A N D O K K U M

By historical standards the Universe is a boring place. Most galaxies have settled down into the routine of middle age and

have all but given up on exciting activities such as forming new stars or fuelling black holes. Studying the light of very distant galaxies with powerful telescopes, astronomers are finding that things were a lot more interesting in the first third of the Universe’s history. The most striking aspect of galaxies in those early epochs is their variety1,2. Some were forming stars hundreds of times faster than the Milky Way; others were dominated by accretion flows onto extremely massive black holes in their centres; and still others were crashing into one another to form larger galaxies. At the same time, a class of compact, massive galaxies existed

that had already stopped forming new stars. Writing in The Astrophysical Journal, van der Wel et al.3 now argue that the majority of these galaxies were disk-shaped.

These compact, massive galaxies are among the most puzzling objects in the young Uni-verse. They seem to have the same number of stars as fully grown galaxies in the present-day Universe. However, their sizes are four to five times smaller and their densities are a hundred times larger4,5 than their present-day counterparts. The surprising discovery of these galaxies a few years ago spurred a flurry of studies, which aim to understand how these massive, compact galaxies formed and how they subsequently managed to grow into the much puffier galaxies we have today.

The installation of a new, very sensitive camera on the Hubble Space Telescope in

Figure 1 | Formation of a compact disk galaxy. According to van der Wel et al.3, most compact massive galaxies in the young Universe were disk-shaped. During their formation, these galaxies probably resembled the nearby galaxy M82, seen here. The blue light is from young stars in a spinning disk. The red light is from ionized hydrogen gas that is being expelled from the galaxy as a result of supernova explosions. Compact disk galaxies forming in the young Universe may have looked even more spectacular than M82, as they were about the same size but ten times more massive.

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disks would mostly have consisted of molecu-lar hydrogen and helium, which would in turn imply that they converted gas to stars at a fero-cious rate while feeding rapidly growing black holes in their centres. It may be possible to detect and characterize these truly spectacular early phases of massive galaxy formation with the Atacama Large Millimeter Array, which is under construction in Chile. ■

Pieter van Dokkum is in the Department of Astronomy, Yale University, New Haven, Connecticut 06511, USA.e-mail: pieter.vandokkum@yale.edu

2009 offers astronomers the ability to study these remarkable galaxies in much greater detail than before. In their study, van der Wel and colleagues3 went beyond a simple size measurement and determined the morpholo-gies of 14 compact galaxies at a time when the Universe was only about 3 billion years old. The authors concentrated on the degree of flattening of the galaxies. Today’s massive gal-axies are essentially big balls of stars and tend to be nearly round, whereas lower-mass galax-ies such as the Milky Way tend to be elongated because their structure is dominated by a flat, spinning disk of gas and stars. Confirming earlier studies5,6 the authors find that a subset of the massive compact galaxies appear highly flattened. Taking into account that some of the apparently round galaxies could be flat disks seen from the top rather than from the side, van der Wel and co-authors argue that most compact galaxies in the young Universe could in fact be spinning disks (Fig. 1).

The case is not yet conclusively proved, because a much larger sample of galaxies needs to be studied to robustly measure the average elongation of compact galaxies. Furthermore, the galaxies may be cigar-shaped (prolate spheroids) rather than disk-shaped. Van der Wel et al. argue that prolate galaxies are rare in today’s Universe, but so are rapidly rotat-ing, extremely compact disks. The real test is whether these galaxies do, in fact, rotate, which would confirm that they are disks. Such a test is just beyond the capabilities of today’s tel-escopes7, but it may be possible to measure the rotation of a similar object that is closer to us, or of a galaxy that happens to be gravita-tionally lensed — that is, has its light bent and magnified — by a foreground object.

If it is confirmed that these distant galaxies are indeed disks, they would be unlike any-thing seen in the Universe today. On the basis of the sizes of the galaxies and their masses, the implied rotation speed would be an astonish-ing 700 kilometres per second. To put this into perspective, the Sun moves around the centre of the Milky Way at a relatively sedate pace of about 230 kilometres per second. This is all the more remarkable given that today’s descend-ants of the compact galaxies are thought to be elliptical galaxies, which do not rotate much at all. It may be that the disks did not survive for long. They may have been destroyed in collisions with other galaxies, which probably occurred frequently during the 10 billion years separating compact galaxies from elliptical galaxies. Some of the disk signatures might be expected to survive this onslaught, and in this context it is interesting that the central regions of elliptical galaxies are often kinematically distinct from the outer regions8,9.

The existence of compact disks of stars in the young Universe would also imply the exist-ence of similarly compact disks of gas at even earlier times — in the first billion years after the Big Bang. Given their densities, these gas

1. Papovich, C. et al. Astrophys. J. 640, 92–113 (2006).

2. Kriek, M., van Dokkum, P. G., Franx, M., Illingworth, G. D. & Magee, D. K. Astrophys. J. 705, L71–L75 (2009).

3. van der Wel, J. et al. Astrophys. J. 730, 38–41 (2011).

4. Daddi, E. et al. Astrophys. J. 626, 680–697 (2005).5. van Dokkum, P. G. et al. Astrophys. J. 677, L5–L8

(2008).6. McGrath, E. J., Stockton, A., Canalizo, G., Iye, M. &

Maihara, T. Astrophys. J. 682, 303–318 (2008).7. van Dokkum, P. G., Kriek, M. & Franx, M. Nature 460,

717–719 (2009).8. Franx, M. & Illingworth, G. D. Astrophys. J. 327,

L55–L59 (1988).9. Krajnović, D. et al. Mon. Not. R. Astron. Soc. 390,

93–117 (2008).

C E L L S I G N A L L I N G

Why fasting worms age slowlyLipids of the N-acylethanolamine family mediate cell signalling across a wide range of organisms. In nematode worms, they translate food availability into fundamental choices about development that affect lifespan. See Letter p.226

L U C I A N O D E P E T R O C E L L I S & V I N C E N Z O D I M A R Z O

Whether prolonged dietary restric-tion can extend human life remains controversial. But this matter has

been settled in the case of some invertebrates, including the widely investigated nematode Caenorhabditis elegans1. A study by Lucanic et al.2 on page 226 of this issue now suggests that decreased signalling by small lipids called N-acylethanolamines is responsible for the lifespan-extending effects of dietary restriction in C. elegans.

N-Acylethanolamines (NAEs) were first identified in the 1950s, but evidence for their signalling role emerged only when a member of this lipid family, N-arachidonoyl-ethanolamine (anandamide), was detected in pig brains3 and recognized as an endocannabi-noid — an endogenous activator of CB1 can-nabinoid receptors. It is now known that these small lipids, which have fatty-acid chains of varying length and saturation level, are wide-spread in both the plant and animal kingdoms, and are even found in single-celled protists. In mammals, signalling through CB1 receptors by anandamide — and another endocannabi-noid, 2-arachidonoyl glycerol — is essential for stimulating food intake following a short period of food deprivation4. This observation provided the rationale for the development of CB1 blockers as anti-obesity agents4.

A relationship between an organism’s energy status and its brain levels of endocannabinoids is not restricted to mammals, but is also found

in non-mammalian vertebrates such as fish, in which these compounds also stimulate food intake (Fig. 1). In the primitive invertebrate Hydra vulgaris, which does not seem to have a protein related to cannabinoid receptors, anandamide nonetheless inhibits feeding behaviour (mouth opening). And the chor-date Ciona intestinalis, which represents the phylogenetic branching point between inver-tebrates and vertebrates, expresses a receptor that is homologous to the human CB1 receptor. In this animal, synthetic CB1 agonists retard mouth reopening after closure4.

The discovery of anandamide3 ignited inter-est in other NAEs, although it was immediately clear that most of these compounds do not share anandamide’s high affinity for CB1 recep-tors. In rodents, N-oleoyl ethanolamine acti-vates PPAR-α, a nuclear receptor that acts as a transcription factor, inhibiting food intake5. But apart from studies on this compound, and on the potent anti-inflammatory mediator N-palmitoyl ethanolamine, research in ani-mals on NAEs that do not bind to cannabinoid receptors has been sparse, unlike work on the signalling function of these lipids in plants6,7. Notably, NAE biosynthetic pathways, and the enzymes that inactivate these compounds, are similar in animals and plants7.

Lucanic and colleagues2 identify NAEs in C. elegans, and demonstrate that the abun-dance of these lipids is reduced under dietary restriction. Moreover, they show that NAE deficiency — due either to impaired biosynthe-sis or enhanced degradation in mutant worm strains — is sufficient to enhance longevity.

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