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is seen in patients with multiple exostoses.Paradoxically, however, there is no evidenceto date that Ihh signals directly across thegrowth plate to the PTHrP-expressing cells; rather, available data indicate that Ihh-expressing cells signal to the adjacentperichondrium, which in turn signals to the PTHrP cells, probably through a bonemorphogenetic protein13.

Because affected people develop bonetumours, EXT-1 and EXT-2 could betumour-suppressor genes, mutation of bothalleles of either locus being necessary fortumour formation3. This interpretation fitswith the aetiology of the disease, but theinsights by Bellaiche and colleagues2 into theprobable role of the EXT proteins, based ontheir analysis of Drosophila ttv, raise a ques-tion mark over such a model. If either EXTprotein is required for diffusion of Ihh, itselimination might be expected to cause pre-mature exit of chondrocytes from the cellcycle, rather than their unrestrained prolif-eration, which presumably results in exo-stoses. In fact, analysis14 of EXT-1-associatedmalignancies argues against the simpletumour-suppressor model — loss of het-

erozygosity in an exostoses-derived chon-drosarcoma is due to elimination of themutant, not the wild-type, EXT-1 allele. So,complete loss of function of EXT-1 is not aprerequisite for tumour formation. There ismuch still to be learned about this interestingcondition, but as the work of Bellaiche et al.has shown, further clues from Drosophilawill doubtless help.Philip W. Ingham is in the Developmental GeneticsProgramme, The Krebs Institute, University ofSheffield, Firth Court, Sheffield S10 2TN, UK.e-mail: p.w.ingham@sheffield.ac.uk1. Ingham, P. W. EMBO J. 17, 3505–3511 (1998).

2. Bellaiche, Y., The, I. & Perrimon, N. Nature 394, 85–88 (1998).

3. Ahn, J. et al. Nature Genet. 11, 137–143 (1995).

4. Stickens, D. et al. Nature Genet. 14, 25–32 (1996).

5. Porter, J., Young, K. & Beachy, P. Science 274, 255–259 (1996).

6. Chen, Y. & Struhl, G. Cell 87, 553–563 (1996).

7. Perrimon, N., Lanjuin, A., Arnold, C. & Noll, E. Genetics 144,

1681–1692 (1997).

8. Taylor, A. M., Nakano, Y., Mohler, J. & Ingham, P. W. Mech.

Dev. 43, 89–96 (1993).

9. Tabata, T. & Kornberg, T. B. Cell 76, 89–102 (1994).

10.McCormick, C. et al. Nature Genet. 19, 158–161 (1998).

11.Solomon, L. J. Bone Joint Surg. 45B, 292–304 (1963).

12.Vortkamp, A. et al. Science 273, 613–622 (1996).

13.Zou, H., Wieser, R., Massagué, J. & Niswander, L. Genes Dev.

11, 2191–2203 (1997).

14.Hecht, J. et al. Am. J. Hum. Genet. 60, 80–86 (1997).

Massive stars inject metal-enriched gasinto interstellar space when they undergosupernova explosions. Pressure-driven out-flows from galaxies then blow this debris intothe IGM (Fig. 1). That should affect the chem-istry and temperature around early quasarsand star-forming objects, but regions of theIGM far from these objects should have littleheavy-element ‘pollution’. The best place tolook for pristine gas is in voids between galaxyclusters: hydrodynamical simulations3,4 pre-dict that gravitational instabilities createdlarge filamentary structures in the IGM. Mas-sive galaxies formed in the dense filaments ofgas and dark matter, and low-density gas filledthe voids between the filaments. Large-scaleredshift surveys bear out this picture (Fig. 2).

Because most star formation and metalproduction probably occurred in the densestregions of the Universe, the low-density voidsbetween galaxies should be the cosmologicalfrontier, with the lowest metal abundance5,6.Indeed, until a few years ago, all weaklyabsorbing hydrogen clouds were thought tobe pristine matter7 consisting only of primor-dial hydrogen and helium. The strongesthydrogen absorbers were later shown8,9 tocontain traces of carbon and silicon ions, andwere taken as indirect evidence for the escapeof enriched gas from ancient galaxies.

To test this further, Cowie and Songailatook the spectra of six quasars at redshifts z >3, looking for weak absorption lines causedby the gas along our line of sight — the linesfrom triply ionized carbon (C IV) and neutralhydrogen (H I). From a pixel-by-pixel com-parison of the carbon and hydrogen absorp-tion, they find that the C IV/H I abundanceratio is roughly the same in all gas clouds,down to the weakest levels that can be

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NATURE | VOL 394 | 2 JULY 1998 17

Astronomers are looking for the firstgeneration of stars and galaxies, andfor their imprint on the chemistry of

the Universe. It is a quest with a frontier spirit about it. Cosmological nucleosyn-thesis models1 predict that the elements toemerge from the Big-Bang fireball werehydrogen, helium and traces of deuteriumand lithium. Heavier elements (called ‘metals’ by astronomers) such as carbon,oxygen, silicon and iron, only formed muchlater, inside stars. But on page 44 of this issue,

Cowie and Songaila2 discuss new data fromthe High Resolution Spectrometer on theKeck 10-metre telescope that hint that thelow-density intergalactic medium (IGM) isfar more metal-rich than expected. Wherecould these heavy elements have come from?

Extragalactic astronomy

Intergalactic pollutionJ. Michael Shull

Figure 1 Simulation6 of the gas density around a star-forming galaxy at redshift z = 9. The box size is 200 kpc (for a Hubble constant of 100 km s−1 Mpc−1); white symbols are stars.Heavy elements would be dispersed by theoutflows predicted here.

N. Y

U. G

NE

DIN

CFA

RE

DSH

IFT

SU

RV

EY

Figure 2 A slice of the local galaxy distribution. Distinct ‘walls’ and ‘voids’ can be seen, on a scale ofup to about 50 megaparsecs (equivalent to more than 3,000 km s–1). Sightlines to nearby quasars, usedas probes of the intervening gas13, are also shown.

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measured (corresponding to the most tenu-ous regions). Earlier analyses of C IV/H I

ratios10,11 also yielded a value, ~ 0.003 timesthat in the Sun, that is approximately constant with H I column density for thehigher-density clouds.

This seems to go against the theory thatvoid gas should be pristine. What couldexplain its enrichment? At z = 3 the Universeis about two billion years old, and in thattime heavy elements expelled from earlystar-forming galaxies at 300 km s−1 wouldonly have moved a small fraction of the 5–10-megaparsec size of the galaxy voids (Fig. 2).The first star-forming objects might havegenerated ‘super-winds’, travelling at morethan 1,000 km s−1, that took metals to greaterdistances and thereby smoothed out themetallicity contrast between galaxy wallsand voids. Alternatively, the voids may beinhabited by dwarf galaxies that easily shedtheir gas and metals following a flurry ofmassive-star formation and supernovae, andthen fade. Or could there have been a widelydistributed generation of ‘population III’early stars that formed before the segregationinto voids and filaments, and polluted theUniverse to a nearly uniform metallicity?

But perhaps this is all a false alarm. Usinga different statistical technique, and addingtogether about 300 weak C IV lines from gason our lines of sight towards nine quasars, Luet al.12 see a lower carbon abundance in thelow-matter-density IGM than in the high-density areas. They believe that their data canrule out the population-III idea.

It is tempting to presume that one of thegroups is wrong. But it could be that the IGMhas a wide distribution of heavy-elementabundances that neither group has adequate-ly characterized. Like blind men describingan elephant, different observers may be prob-

ing different parts of the IGM density andmetallicity distribution, and failing to get agood picture of the whole. Each group shouldlook carefully at the other’s analysis tech-niques (they have two quasars in common)and continue the debate. Depending on howit is resolved, astronomers may need to revisetheir views on the first epoch of star forma-tion and the physical mechanisms that returngas to intergalactic space.

The new Keck results push the limits ofspectroscopy, with integration times of 4 to11 hours, reaching 100:1 signal-to-noiseratios towards 16–17th-magnitude quasars.They highlight the need to characterizedetector noise and to devise statistical tech-niques that dig out weak features. New 10-metre telescopes will soon be joining thequest, and astronomers are planning newinfrared, X-ray and ultraviolet instrumentsto search for other traces of the first genera-tions of star-forming galaxies.J. Michael Shull is in the Department ofAstrophysical and Planetary Sciences, University ofColorado at Boulder, Boulder, Colorado 80309, USA.e-mail: mshull@casa.colorado.edu1. Copi, C. J., Schramm, D. N. & Turner, M. S. Science 267,

192–199 (1995).

2. Cowie, L. L. & Songaila, A. Nature 394, 44–46 (1998).

3. Zhang, Y., Meiksin, A., Anninos, P. & Norman, M. L. Astrophys.

J. 485, 496–516 (1997).

4. Hernquist, L., Katz, N., Weinberg, D. H. & Miralda-Escudé, J.

Astrophys. J. 471, 582–616 (1996).

5. Gnedin, N. Yu. & Ostriker, J. P. Astrophys. J. 486, 581–598 (1996).

6. Gnedin, N. Yu. Mon. Not. R. Astron. Soc. 294, 407–421 (1998).

7. Sargent, W. L. W., Young, P. J., Boksenberg, A. & Tytler, D.

Astrophys. J. Suppl. Ser. 42, 41–81 (1980).

8. Cowie, L. L., Songaila, A., Kim, T.-S. & Hu, E. M. Astron. J. 109,

1522–1530 (1995).

9. Tytler, D. et al. in QSO Absorption Lines (ed. Meylan, G.)

289–298 (Springer, Berlin, 1995).

10.Songaila, A. & Cowie, L. L. Astron. J. 112, 335–351 (1996).

11.Giroux, M. L. & Shull, J. M. Astron. J. 113, 1505–1513 (1997).

12.Lu, L., Sargent, W. L. W., Barlow, T. A. & Rauch, M. Astron. J.

(submitted); preprint astro-ph/9802189 on xxx.lanl.gov (1998).

13. Shull, J. M., Stocke, J. T. & Penton, S. Astron. J. 111, 72–77 (1996).

ing an mGluR. This receptor, in turn, inhibitsthe activity of a cation channel.

The inhibitory action of glutamate canalso be mediated by a chloride channel that is associated with a high-affinity glutamatetransporter6, or by activation of potassiumchannels7,8. Accordingly, synaptically re-leased glutamate in the brain was expected toshow inhibitory actions, and Fiorillo andWilliams3 now report the first example ofthis. They have characterized a mGluR(mGluR1) which, by activating phospho-lipase C (PLC; the enzyme that catalyses production of the second messengers inosi-tol-1,4,5-trisphosphate and diacylglycerol),activates an apamine-sensitive potassiumchannel (Fig. 1, overleaf).

Why has this inhibitory action of gluta-mate rarely been detected before? It could be that it is a specific property of only a fewglutamatergic synapses, although that inturn may seem to occur simply because theinhibitory effect can be observed only underparticular conditions. For example, Fiorilloand Williams did not observe the effect whenselective agonists for mGluR1 were appliedin the bath (slow application) — instead,they found a very slowly developing excita-tion (depolarization). This agrees withobservations by others2,9 and with the gen-eral idea that PLC-coupled receptors exertpotentiating effects by inhibiting potassiumchannels or activating non-selective cationchannels (Fig. 1).

Fiorillo and Williams also foundmGluR1-mediated excitation upon synapticrelease of glutamate, but after the inhibitoryphase. Only fast application of mGluR ago-nists can generate the inhibitory action (Fig.1), and the authors propose that the intra-cellular cascade responsible for the inhibi-tion desensitizes rapidly. In other words, allof the receptors have to be activated at thesame time to generate this response. So, these findings indicate that the same receptor can mediate either excitatory or inhibitoryeffects depending on the kinetics of its stimulation.

A similar switch between positive andnegative effects mediated by a PLC-coupledmGluR has also been reported at the pre-synaptic level. Sanchez-Prieto and col-leagues used biochemical methods to show10

that activation of a presynaptic PLC-coupledmGluR could potentiate the release of gluta-mate. More recently, these authors havedemonstrated11 that the potentiating effectthat they previously described is turned intoan inhibitory effect if the PLC responsemediated by this receptor is desensitized.They did this by first activating the receptor(or by constantly activating it) with a lowconcentration of glutamate. So, as at thepostsynaptic side, depending on how thepresynaptic PLC-coupled mGluRs are acti-vated, they will exert either an inhibitory or apotentiating effect. This may explain why a

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NATURE | VOL 394 | 2 JULY 1998 19

Most fast, excitatory synapses in thebrain use the common neurotrans-mitter glutamate, which activates

both ionotropic and metabotropic gluta-mate receptors (iGluRs and mGluRs).Because mGluRs are located on both pre-and postsynaptic elements, they are impor-tant in regulating the strength and frequencyof synaptic firing, including the long-termmodification of synaptic strength. Surpris-ingly few effects resulting from activation ofthe mGluRs by synaptically released gluta-mate have been identified1,2 but, on page 78of this issue, Fiorillo and Williams3 reveal anew one. They have found that one mGluRthat was assumed to be mainly excitatory can generate a large inhibitory action uponrelease of glutamate.

Inhibition by glutamate (hyperpolariza-tion) has been known for some time in inver-tebrates. At the neuromuscular junction ofinsects, glutamate excites nerve cells toinduce contraction — just as acetylcholinedoes for contraction of our own muscles.However, extrasynaptic glutamate receptorslocated on insect muscles have a hyperpolar-izing action that results from activation of achloride channel4. In mammals, glutamate is also the transmitter in a well-knowninhibitory synapse in the retina5. Thissynapse — between the photoreceptor celland the ON bipolar cell — is responsible forthe signal recorded from the retina when lightis switched on. In the dark, constant release ofglutamate by the photoreceptor cells inhibitsthe activity of the ON bipolar cells by activat-

Synaptic transmission

The two faces of glutamateJean-Philippe Pin