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Mating, channels and kidney cysts
Author: Scott W. Emmons
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"� 1999 Macmillan Magazines Ltd looked like the ?normal? Pacific. Figure 1 shows the behaviour of the subsurface water in the Indian and Pacific Oceans at a time when both oceans were in a highly anom- alous state. It is tempting to think that it is no coincidence that a very strong dipole in the Indian Ocean occurred at the same time as one of the largest El Ni�os on record. But both Webster et al. 1 and Saji et al. 2 argue oth- erwise. They show that the conditions of 1997?98 are not unprecedented and that large amplitudes of the dipole occurred in 1961 (ref. 7), 1967, 1972 and 1994. Dipole variability is present to some degree most of the time but what kicks it into top gear is not clear. There is little statistical relationship between the Indian Ocean dipole and El Ni�o: the dipole occurs in both El Ni�o and non-El-Ni�o years, and Saji et al. show that it has also been evident even in a weak La Ni�a year such as 1967 (La Ni�a, the con- verse of El Ni�o, is when the east Pacific is anomalously cold). Based on six major dipole events in the past 40 years, Saji et al. 2 have constructed a composite picture of the dipole mode show- ing its spatial structure at different phases. Their Fig. 2 (page 361) highlights the impor- tance of wind and temperature changes first in the Indonesian region, initially to the south of the Equator but then, later, in Sep- tember?October, westward along the Equa- tor (sometimes, as in 1997, as far as Africa). They show that the dipole mode has a bien- nial character which may imply a certain pre- dictability from one year to the next. The reliability and so usefulness of such predic- tions is likely to be limited, however, as we simply don?t know how the dipole fits into the larger picture of climate variability and factors such as Himalayan snow cover and chaotic processes that are not directly linked to slow changes in sea-surface temperature. How the dipole is related to monsoon rainfall is also unclear 8 ; of the two biggest dipole events, that of 1961 was associated with the heaviest monsoon in 150 years 2 , whereas in that of 1997 rainfall over India was normal 9 . In fact, Saji et al. find no statis- tical relationship between monsoon rainfall and the dipole. Nonetheless, the observa- tions and analysis reported by Webster et al. and Saji et al. mean that the Indian Ocean jumps several rungs up the climate ladder of importance. We are still some way from understanding rainfall around the Indian rim, one of Lockyer?s original goals, but identification of variability such as the dipole mode is a considerable step forward. n David Anderson is at the European Centre for Medium-Range Weather Forecasts, Shinfield Park, Reading RG2 9AX, UK. e-mail: sta@ecmwf.int 1. Webster, P. J., Moore, A. M., Loschnigg, J. P. & Leben, R. R. Nature 401, 356?360 (1999). 2. Saji, N. H., Goswami, B. N., Vinayachandran, P. N. & Yamagata, T. Nature 401, 360?363 (1999). 3. Kininmonth, W. The 1997?98 El Ni�o Event: A Scientific and Technical Retrospective (World Meteorological Organisation, Geneva, in the press). 4. Anderson, D. & McCreary, J. J. Atmos. Sci. 42, 615?625 (1986). 5. Birkett, C., Murtugudde, R. & Allan, T. Geophys. Res. Lett. 26, 1031?1034 (1999). 6. Bjerknes, J. Mon. Weath. Rev. 97, 163?172 (1969). 7. Reverdin, G., Cadet, D. & Gutzler, D. Q. J. R. Meteorol. Soc. 112, 43?68 (1986). 8. Nicholls, N. J. Clim. 8, 1463?1467 (1995). 9. Bell, G. & Halpert, M. Bull. Am. Meteorol. Soc. 79, S1?S50 (1998). 10.www.ecmwf.int news and views NATURE | VOL 401 | 23 SEPTEMBER 1999 | www.nature.com 339 A dvances in human genetics have meant that the genes mutated in human dis- eases can be identified exclusively by their location in the genome. But how do we work out the cellular functions of the associ- ated protein products? Reports on pages 383 and 386 of this issue 1,2 begin to address this problem for two proteins ? polycystin-1 (PKD1) and polycystin-2 (PKD2) ? that are defective in human autosomal dominant polycystic kidney disease. From their studies of the nematode worm Caenorhabditis ele- gans, Barr and Sternberg 2 present evidence that homologues of the polycystins act together in a signal-transduction pathway in sensory neurons. Chen et al. 1 , by contrast, have used an oocyte-expression system in the frog Xenopus laevis to show that a homo- logue of PKD2 is associated with the activity of a cation channel. These results support the hypothesis that polycystin-related proteins belong to a hitherto unknown class of signal- transduction molecules. Autosomal dominant polycystic kidney disease affects more than one in 1,000 live births, and is the most common single-gene disorder leading to kidney failure. The chil- dren of affected parents have a one in two chance of inheriting the disease, and half of all sufferers need dialysis or a kidney transplant by the age of 60. Mutations in either PKD1 or PKD2 cause almost indistinguishable clinical symptoms. Although the kidney is the most severely affected organ, the disease is systemic and affects the liver, pancreas and cardio- and cerebro-vascular systems as well. The PKD1 protein is a roughly 4,300- amino-acid integral-membrane glycopro- tein with a large, amino-terminal extracellu- lar domain and a small, carboxy-terminal Signal transduction Mating, channels and kidney cysts Scott W. Emmons and Stefan Somlo Figure 1 Two components of the proposed polycystin signalling pathway. Proteins related to human PKD1 (refs 3, 4) include the C. elegans LOV-1, studied by Barr and Sternberg 2 , the sea-urchin egg jelly receptor (suREJ) 8 and its human homologue PKDREJ (ref. 9). The large, extracellular domains contain different binding motifs: REJ module (blue); immunoglobulin-like PKD repeats (yellow); leucine-rich repeats and C-lectin-like domain (pale orange); serine/threonine-rich mucin-like domain (purple); ATP/GTP-binding domain (dark orange). The small cytoplasmic tails are thought to mediate interaction with proteins related to human PKD2 (ref. 5), including the polycystin-like (PCL) protein studied by Chen et al. 1 and the C. elegans PKD-2. PKD2-related proteins are predicted to have six membrane spans (dark blocks) and a cytoplasmic EF-hand (open block). The dark blocks in the PKD1-related protein represent the region of sequence similarity with PKD2-related channels. NH 2 Ca 2+ (Na + , K + ) COOH Acrosome reaction (sea urchin, human?) Location of vulva/response (C. elegans) ? (Cyst formation in the kidney ? human, mouse) ? Ligands s u R E J / P K D R E J P K D 1 L O V - 1 Extracellular portion Intracellular portion Cell membrane PKD2 PCL PKD-2 COOH � 1999 Macmillan Magazines Ltd cytoplasmic tail 3,4 . The predicted structure of its domains suggested that it is involved in cell?cell interactions or in interactions with the extracellular matrix. The PKD2 protein has similarities to PKD1, but its topology and domain structure suggest that it might act as a subunit of a cation (perhaps calcium) channel 5 . An important clue to the relation- ship between PKD1 and PKD2 came from the discovery that they interact directly, sug- gesting that they act in a common pathway 6,7 . The possibility of a widespread function of related pathways was first suggested by the discovery of a structural relationship between PKD1 and a membrane receptor in sea-urchin sperm. This receptor mediates the acrosome reaction ? an ion-channel- regulated membrane fusion event that is necessary for fertilization 8 . Human testes express a similar polycystin-related protein 9 . Now, quite unexpectedly, Barr and Stern- berg 2 find that a mutation in C. elegans, which gives rise to males that are defective in mating behaviour, lies in a gene called lov-1 (for ?location of vulva?) ? the worm homo- logue of human PKD1. Since research on C. elegans was initiated by Sydney Brenner in the late 1960s, work on this animal has, in part, been directed at understanding the genetic basis of development and the func- tion of its nervous system. Male mating ? in which males seek out the hermaphrodite partner and copulate with her ? is probably the most complex behaviour shown by C. elegans. Sternberg?s laboratory had previously defined the six sub-steps of the stereotyped copulatory sequence, correlated these sub- steps with the function of individual neu- rons, and isolated behavioural mutants 10 . One of the sub-steps is to locate the vulva. As well as being unable to execute this step effi- ciently, lov-1 mutant males are also defective in the first sub-step, termed ?response?. Response and vulva location depend on two types of male sensory structure. The first is a set of nine pairs of rays, which project out of the tail on each side. The second is a hard- ened cuticular structure called the hook, which contains two sensory neurons. Knowing that PKD1 and PKD2 interact, Barr and Sternberg next used the recently completed C. elegans genome sequence to isolate pkd-2, the worm homologue of human PKD2. They then studied the expres- sion patterns of both lov-1 and pkd-2, and found that promoter sequences of both genes cause reporter genes to be expressed in the rays and the hook sensory neurons required for response and vulva location. Arguing (from a variety of evidence) that the defect in the lov-1 mutant is not develop- mental, the authors concluded that the LOV-1 and PKD-2 proteins are involved in chemosensory or mechanosensory signal transduction in sensory neurons. By contrast, Chen et al. 1 used cell-expres- sion and electrophysiological approaches to examine the potential channel function of a polycystin-related protein. This protein, called PCL (polycystin-like), had been iden- tified in the human expressed-sequence-tag database by its sequence similarity with that of PKD2. Although its function was not known, the authors knew that PCL, like PKD2, has the structural fingerprint of a cation-channel subunit related to a number of families (the transient receptor potential calcium channel and voltage-gated calcium-, sodium- and potassium-channel families). The PCL and PKD2 proteins both contain a calcium-binding EF-hand domain that may help to regulate channel activity. Chen et al. expressed PCL in Xenopus oocytes by microinjecting synthetic messen- ger RNA for the protein. They then studied its channel properties using the two-micro- electrode voltage clamp and patch-clamp techniques. The authors found that PCL is a non-selective cation channel that is perme- able to sodium, potassium and calcium. Its calcium permeability is about five-fold high- er than that of sodium, and calcium modu- lates the channel?s activity. However, Chen et al. could not determine whether binding at the EF-hand domain is responsible for this calcium regulation. The high structural similarity between PCL and PKD2 provides indirect evidence that PKD2 is also a cation- channel subunit. These data support the hypothesis that PKD1-related proteins act as receptors that regulate the activity of channels containing PKD2-related proteins (Fig. 1). The two pro- teins are part of a conserved signalling mech- anism in which the translocation of ions acts as a second messenger. But the diversity of the processes in which this signalling mecha- nism seems to be involved highlights the remaining questions. What are the specific molecular cues that activate these pathways? What are their downstream effectors? And what additional factors are responsible for adapting this mechanism to the unique requirements of each tissue? n Scott W. Emmons is in the Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. e-mail: emmons@aecom.yu.edu Stefan Somlo is in the Section of Nephrology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8029, USA. e-mail: stefan.somlo@yale.edu 1. Chen, X. Z. et al. Nature 401, 383?386 (1999). 2. Barr, M. M. & Sternberg, P. W. Nature 401, 386?389 (1999). 3. Hughes, J. et al. Nature Genet. 10, 151?160 (1995). 4. The International Polycystic Kidney Disease Consortium Cell 81, 289?298 (1995). 5. Mochizuki, T. et al. Science 272, 1339?1342 (1996). 6. Qian, F. et al. Nature Genet. 16, 179?183 (1997). 7. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V. P. & Walz, G. Proc. Natl Acad. Sci. USA 94, 6965?6970 (1997). 8. Moy, G. W. et al. J. Cell Biol. 133, 809?817 (1996). 9. Hughes, J., Ward, C. J., Aspinwall, R., Butler, R. & Harris, P. C. Hum. Mol. Genet. 8, 543?549 (1999). 10.Liu, K. S. & Sternberg, P. W. Neuron 14, 79?89 (1995). news and views 340 NATURE | VOL 401 | 23 SEPTEMBER 1999 | www.nature.com Daedalus Fertile competition The claim has been made that sperm counts in the West are declining alarmingly. A typical ejaculate might contain 100 million sperm; since only one is required to do the job, a reduction to (say) 50 million may not seem obviously critical. But human fertilization is chancy at best. Even trying hard, a couple can easily take many months to conceive. One explanation is that most sperm are infertile. Their job is to ward off or discourage rival sperm. In effect, they act as a large screen of warships escorting a small, crucial convoy of freighters. Daedalus argues that both freighters and warships will put on a mighty spurt if challenged by a rival fleet. There is some evidence that a man with a sexual rival generates more sperm than he would do otherwise; but Daedalus reckons that the speed, efficiency and pugnacity of his sperm must rise as well. In many species sperm compete chemically, by putting out toxins or antigens against their rivals. Indeed, Daedalus once proposed to use human seminal toxins in a natural spermicidal contraceptive. He now has a converse strategy. DREADCO biochemists are studying human seminal toxins in the hope of developing a spermal ?vaccine?. It will be a derivative of such a toxin, modified just enough to be harmless, but still sensed as a deadly threat by sperm encountering it. Spurred by this challenge, they will drive towards the ovum with extra speed and energy. This ingenious ?conceptive? will be welcomed by couples trying hard to have children. It will boost their chances greatly. But Daedalus goes further. The sperm in a given ejaculate must be immune to their own toxin. They should even tolerate quite well the toxin of a close genetic relative carrying many of the same genes. But toxin from a genetic stranger must be a terrible threat. The DREADCO team are therefore mixing semen samples from different types and races of men, and studying their competition under the microscope. They will then plot the semen donors on a map such that the more fiercely antagonistic the sperm of any two donors, the further apart they are on the map. The resulting human distribution will be far more fundamental than one based (say) on blood groups or pigmentation. It will reveal the classes of mankind as sensed by genetics itself. It should powerfully illuminate the stages by which we emerged from Africa, and our diversification since then. David Jones "
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