represses expression of the aquaporin-7gene6,7. In the insulin-resistant condition, how-ever, the sustained increase of aquaporin-7production in fat tissue perturbs glucose balance by producing an abnormal increase inglucose production in the liver.

Further characteristics of the older knockoutmice were low bloodstream levels of glyceroland of adiponectin, a secretion product of fatcells that mediates insulin action (Fig. 1). Con-versely, these mice had high blood concentra-tions of glucose, insulin, free fatty acids andleptin (leptin participates in body-weight regu-lation through its effects on the hypothalamus,the brain region that controls feeding behav-iour, body temperature and energy output).Hibuse et al. found that these metabolic pertur-bations were more severe in aquaporin-defi-cient mice fed a high-fat diet. In tying thesevarious observations together, there is evidentlya need to invoke the existence of a coordinatedregulation of fat-cell-specific and liver-cell-specific glycerol channels in determining glucose metabolism and insulin resistance8.

Ten-week-old knockout mice, by contrast,did not show these various symptoms1. They

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were not insulin resistant, and had low levels ofglucose in the bloodstream. This was probablydue to reduced glycerol transport to the liverand inefficient glucose production there —despite the increased expression of phospho-enolpyruvate carboxykinase, the key liverenzyme in the pathway that generates glucosefrom non-carbohydrate substrates such asglycerol9.

All in all, these three studies1–3 provide firmevidence that aquaporin-7 is required for glycerol release from fat cells in mice. The latest work1 also shows that this channel is a broader player in glucose balance and sensi-tivity to insulin. But how relevant are the findings for human obesity?

The human gene that encodes aquaporin-7lies on the long arm of chromosome 13, andhas not previously been implicated in obesity.So far, only a single human case of loss-of-function mutation in the aquaporin-7 genehas been reported7: the subject did not becomeobese or diabetic, the only apparent conse-quence being impaired increase of glycerol inthe bloodstream during exercise.

Nonetheless, it might be worth exploring thepossibility of selectively enhancing aquaporin-

HISTOCOMPATIBILITY

Colonial match and mismatchGary W. Litman

Distinguishing self from non-self is the underlying basis of immunity.Intriguingly, the genetic system that governs a natural process akin to tissuetransplantation in vertebrates has been characterized in an invertebrate.

On page 454 of this issue, a remarkable paperby De Tomaso and colleagues1 describes dis-coveries on two different fronts. The authors’subject of study is a small marine organism, atunicate called Botryllus schlosseri (Fig. 1, over-leaf). Their results provide insight into whycolonies of this animal sometimes merge intoone, with a common blood circulation, andsometimes reject that option. Also — andmore notably — the results will raise aware-ness of forms of immune recognition thatextend beyond those known in vertebrates.

The ability of an individual to distinguishtissues of another individual from its own is afundamental characteristic of multicellularanimals2. In humans and other vertebrates,this process, known as allorecognition, is seenin the success or failure of skin grafts andorgan or bone-marrow transplants. Theseinteractions are determined by the products ofa particularly diverse group of genes encodedwithin the major histocompatibility complex,known as MHC-I and -II, which primarilymobilize the immune response to foreign bod-ies, including infections by viruses and bacte-ria. It is their polymorphism — the extensive

7 expression in fat tissue for therapeutic ends.Another obvious project would be to look fordifferences in aquaporin-7 production andfunction between lean and obese individuals.Other steps would be to investigate how themolecular structure of the pore affects its speci-ficity for glycerol, with drug design in mind,and to carry out gene-expression and protein-stability studies to achieve a better basic under-standing of aquaporin action. ■

Gema Frühbeck is in the Department ofEndocrinology, Clínica Universitaria, Universidad de Navarra, 31008 Pamplona, Spain.e-mail: gfruhbeck@unav.es

1. Hibuse, T. et al. Proc. Natl Acad. Sci. USA 102, 10993–10998(2005).

2. Maeda, N. et al. Proc. Natl Acad. Sci. USA 101, 17801–17806(2004).

3. Hara-Chikuma, M. et al. J. Biol. Chem. 280, 15493–15496(2005).

4. King, L. S., Kozono, D. & Agre, P. Nature Rev. Mol. Cell Biol. 5,687–698 (2004).

5. Kuriyama, H. et al. Biochem. Biophys. Res. Commun. 241,53–58 (1997).

6. Kishida, K. et al. J. Biol. Chem. 276, 36251–36260 (2001).7. Kondo, H. et al. Eur. J. Biochem. 269, 1814–1826 (2002).8. Kuriyama, H. et al. Diabetes 51, 2915–2921 (2002).9. MacDougald, O. A. & Burant, C. F. Proc. Natl Acad. Sci. USA

102, 10759–10760 (2005).

Live

r

Glucose

Bloodstream

Glucose

Insulin

Leptin

FFA

Adiponectin

Aquaporin-7

Muscle

Glycerol

Glucose

Fat cell

Glycerol-3-phosphate

Triglycerides

Glycerol FFA

Glycerolkinase

Figure 1 | Consequences of aquaporin-7deficiency1–3. In fat cells, glucose is the substratefor the synthesis of fat deposits in the form oftriglycerides, which can subsequently bemobilized as glycerol and free fatty acids (FFA). Ifthe gene for aquaporin-7 is deleted, fat cells showglycerol accumulation, which results in enhancedglycerol kinase activity and triglyceride synthesis,and fat-cell enlargement. The loss of aquaporin-7-mediated glycerol transport from fat cellsaffects the concentrations of various metabolitesand hormones in the bloodstream, as shown. Theupshot is perturbation of the triglyceride–fatty-acid cycle, and of glucose metabolism in the liverand muscle. Dotted arrows indicate pathways;solid arrows indicate increases or decreases inconcentrations.

differences between the products of individualgenes — and their expression in tissuesthroughout the body that make these particu-lar MHC products such central players in vertebrate histocompatibility reactions.

In the animal world, only jawed vertebratespossess MHC-I and -II. Naturally occurringallogeneic interactions have, however, beenwell documented in protochordates and thenon-chordate invertebrates (see Box 1 for fur-ther explanation). In Botryllus, allorecog-nition is governed at a single genetic locus,FuHC (for fusibility/histocompatibility). DeTomaso et al.1 have now isolated the FuHCgene locus and provide the first insights intothe molecular basis for this ancient form ofMHC-independent allorecognition.

The fusibility seen in Botryllus involvesampullae, small protrusions at the peripheryof tunicate colonies. When the ampullae fromtwo colonies come into close proximity, theproducts of the FuHC gene locus determinewhether fusion or rejection occurs. Fusionresults when two colonies share at least oneFuHC gene variant, or allele; rejection occurswhen no FuHC alleles are shared. Thus, for

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example, a colony with AA alleles at the FuHClocus would fuse with one with AB, butAA�BB would result in rejection.

Most populations of Botryllus consist ofmany genetically disparate colonies, and tensto hundreds of allelic variants of FuHC prob-ably exist. Individual colonies are preferen-tially maintained as heterozygotes — that is,with two different alleles at the FuHC locus —because of the developmentally regulatedadvantage conferred through heterozygosity3,4.

De Tomaso et al.1 isolated and physicallymapped the Botryllus FuHC locus by classicalgenetic approaches. Its gene product would beexpected to span the cell membrane and behighly polymorphic, as turned out to be thecase; further study showed that it containsunits called epidermal growth factor repeatsand also immunoglobulin domains, but of a different type from those seen in MHC-I and -II. The authors also found that allelicpolymorphism of FuHC was correlated withfusion or rejection in transplantation assays of laboratory strains. They went further byobserving the interaction of wild-type coloniesharvested from different geographical areas,and the results confirmed the absolute concor-dance of fusibility and genotype.

Botryllus colonies live in close proximity, inthe narrow ecological niches of tidal pools;colony mergers, with the transfer of geneticmaterial, are an essential part of their popula-tion dynamics. The mechanistic basis for thishas long been thought to involve geneticallydetermined stem-cell parasitism5, in whichcells mobilize and transfer between individuals,potentially being able to replace the cells of thehost. The characteristic features of the parasitic

cells are retained upon surgical transplantation(D. J. Laird and A. W. De Tomaso, personalcommunication). The FuHC genes have prob-ably evolved to restrict germline exchange(exchange of genetic material that will bepassed on to the next generation) to closelyrelated individuals as a way of preserving adiverse gene pool that otherwise could becomehomogenized throughout an entire population.This, then, is a fascinating case of potentiallyrapid mechanisms of germline change that isseparate from traditional inheritance. Similareffects probably account for polymorphic histocompatibility in other invertebrates6.

The histocompatibility system revealed byDe Tomaso et al. is evidently essential to thesurvival of Botryllus. Given its importance,does a similar system survive in higher verte-brates? In their paper, the authors draw anal-ogies between fusibility and recognition of‘missing self ’, in which the lack of at least oneinteraction between FuHC and its putativereceptor triggers a rejection response. Inmammals, and probably other higher verte-brates, recognition of missing self is the basisfor immunity mediated by natural killer cells;these typically sense either a decrease in polymorphic MHC-I (a consequence of viralinfection) or an increase in stress-inducedMHC-I-related determinants7, both of whichseem to be absent in another protochordatestudied8. In this and other work that delvesdeep into evolutionary history, the overridingissue is whether the evolutionary trail is clear enough to allow recognition of tradi-tional relationships (such as genetic sequenceidentity, protein structure homologies or

regulatory network similarities). De Tomaso et al.1 have identified polymorphic genes thatmap to within 200 kilobases of the FuHC locusand that could encode a receptor for the FuHCgene product. This finding should clarify therelatedness of fusibility to other self–non-selfrecognition processes.

Irrespective of whether this ancient adapta-tion may live on elsewhere, colonial fusibility isthe best-characterized example of the mecha-nisms that invertebrates, protochordates andjawless vertebrates use to distinguish self fromnon-self. Over the past several years, our eyeshave been opened to a variety of alternativemediators of immune function that haveblurred the traditional distinctions betweeninnate and adaptive immunity9. This latestpaper takes the story further, and is probablydestined to become a classic. It reveals thatgenetically driven allorecognition may havebeen essential in creating and maintaining thefittest gene pools in our ancient ancestors. ■

Gary W. Litman is at the Children’s ResearchInstitute, 830 First Street South, St Petersburg,Florida 33701, USA.e-mail: litmanG@allkids.org

1. De Tomaso, A. W. et al. Nature 438, 454–459 (2005).2. Burnet, F. M. Nature 232, 230–235 (1971).3. Scofield, V. L., Schlumpberger, J. M., West, L. A. &

Weissman, I. L. Nature 295, 499–502 (1982).4. De Tomaso, A. W. & Weissman, I. L. Science 303, 977 (2004).5. Stoner, D. S., Rinkevich, B. & Weissman, I. L. Proc. Natl Acad.

Sci. USA 96, 9148–9153 (1999).6. Buss, L. W. The Evolution of Individuality (Princeton Univ.

Press, 1987).7. Vivier, E. & Malissen, B. Nature Immunol. 6, 17–21 (2005).8. Dehal, P. et al. Science 298, 2157–2160 (2002).9. Litman, G. W., Cannon, J. P. & Dishaw, L. J. Nature Rev.

Immunol. 5, 866–879 (2005).

The following is a summary of the relationshipsamong the animal groups mentioned in thisarticle. The Chordata include the Vertebrata,Cephalochordata and Urochordata, of whichBotryllus schlosseri is a member. The Vertebratainclude both jawed and jawless animals, but theonly surviving members of the latter are thelampreys and hagfishes. The Protochordata arean informal grouping of the Cephalochordataand Urochordata, and another group, theHemichordata. As invertebrate chordates, theProtochordata are not to be confused with thefamiliar non-chordate invertebrates(echinoderms, molluscs, arthropods and so on).

Traditionally, both the invertebrates andprotochordates have been considered topossess innate immunity, which is present from birth and is not highly specific; generalinflammation is an example of an innate immune response. Vertebrates possess bothinnate and adaptive immunity; the latter istriggered in response to a foreign challenge, such as an infection, and is highly specific. Injawed vertebrates, rejection of a foreign tissue graft is mediated by the cellular arm of the adaptive immune system throughinteractions with products of the majorhistocompatibility complex. G.W.L.

Box 1 Chordates and invertebrates

Figure 1 | Botryllus schlosseri: test case in histocompatibility. The Botryllus life cycle includes both a free-living sexual stage and a sedentary, asexual stage in which colonies grow by budding. A colony(pictured here) consists of genetically identical individuals known as zooids, which are sheathed in a gelatinous tunic and are connected by a vascular system. When colonies come into close contact,histocompatibility reactions occur at their peripheries, in small protrusions termed ampullae. Colonieseither fuse (which leads to sharing a vascular system) or reject fusion on the basis of allele compatibilityor incompatibility, respectively, at the FuHC locus. See also Fig. 1 on page 455 of the paper1.

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