the major research focus of the future is, ‘‘how, on amechanistic level, are these microbes accomplishing thesefeats and how can we interfere with these phenomena?’’ Inthe present age of genomics, more and more informationconcerning the potential virulence components of a givenpathogen has become available but the question remains,‘‘what do these components do and which of them areresponsible for the observed outcomes of an infectiousdisease process?’’ The future of pathogenic microbiology, ofimmunology, and of certain aspects of cell biology will de-

pend more and more upon multi-disciplinary approaches.Examining single components of an infectious model isbeing replaced by more inclusive and in-depth exami-nations of the intricate interaction of the many com-ponents involved. Furthermore, the adoption of a variety ofbiochemical as well as physiological approaches hasbegun to and will most certainly continue to contribute toour understanding of the specific mechanisms of host-pathogen interactions. Indeed, there is a great deal to lookforward to.

Cell fate and thegeneration of celldiversityAdam S. Wilkins

What zygotic gene activities initiate the first regional differ-ences in early animal embryos? What are the genes andmolecular processes that produce the stem cell condition?What are the genetic foundations of guided cell migration orgrowth of cell processes? How are individual developmentalregulator molecules deployed for different roles within thesame organism? How much conservation is there not only ofkey developmental regulator molecules but of the networks inwhich they are embedded?

These were some of the general questions addressed inthe talks at a symposium late last year (October 10–13), titled‘‘Cell Fate and the Generation of Cell Diversity’’. The sympo-sium was the 11th in an annual series that is designed to bringtogether major figures in biology with an audience composedpreponderantly of young scientists, especially postgraduatestudents. The conference series is sponsored by the Interna-tional Institute of Genetics and Biophysics (Naples, Italy) andis held on the island of Capri, in the Bay of Naples.

Since developmental biology as a whole is largely devotedto exploration of the two topics in the conference title, namelycell fate and cell diversity, focus was achieved by concentra-tion on a few selected areas. In particular, special attentionwas given to the developmental biology of neural systemsand the specification of patterning along embryonic axes.There was also strong emphasis on a few key model

organisms, in particular Xenopus, the mouse, zebrafish,Drosophila and Caenorhabditis. Space limitations make im-possible a full accounting of the talks at the meeting; whatfollows is a brief description of some of the highlights, withapologies to those whose talks are not mentioned below.

The first talk, by W. Harris (University of Cambridge),dealt with development of the frog retina. Retinal develop-ment begins in the ciliary marginal zone (CMZ), the peripheralzone of cell proliferation, which consists of stem cells and isthe source of new cells for the retina development throughoutthe life of the animal. Not only is there a gradient of cellproliferation from the CMZ to the most central region of theretina, where cell division stops, but there is a correspondingspatial pattern of expression of specific genes. In the mostperipheral part of the CMZ, several genes, including Pax6and Six3 are expressed that are also expressed in the initialeye field of the embryo. More centrally, Xath5 and Xash3 areexpressed and these positively regulate each other; thisexpression zone is followed by a further sequence of geneexpressions along the radii from periphery to center, the mostcentral zone showing expression of specific neuronal/eyedifferentiation genes and cessation of cell division. In thestem cell zone of the CMZ, both Pax6 and Six3 in the CMZmay actively promote cell division, through positive regulationof key cell cycle regulators, while the more downstream andcentrally-activated regulators may have the reverse effect ondifferentiating cells, which have stopped dividing.

In the telencephalon, the most anterior forebrain region,an additional function of Pax6 is to regulate differentialadhesion between different cell types. J. Price (SmithKlineBeecham, Harlow) described the differences between corticallayer and striatal cells that arise during the early developmentof the mouse telencephalon. These two cell types derive froma common precursor pool but they lose their multipotentialitybetween 13 and 16 days of development. During this period,both cell types exhibit a transient but strong self-segregation,as assayed in vitro. This self-segregation is directly mediatedby differential R-cadherin expression, a property regulated byPax6, as shown with Pax6-mutant mice (Small eye or Sey).

Correspondence to: Adam S. Wilkins, BioEssays Editorial Office, 10/11Tredgold Lane, Napier St., Cambridge CB1 1HN, UK.

Meetings

260 BioEssays 21.3

The development of both the eye and the telencephalonare relatively late events in the embryogenesis of the CNS. Alarger set of talks, in contrast, focused on the early events inregional patterning of the CNS. Y. Grinblat (WhiteheadInstitute) compared these early patterning steps in the ze-brafish (Danio rerio) embryo and in the frog Xenopus laevis.She finds that in the zebrafish, patterning of the forebrainbegins during early gastrulation, well before formation of theneural plate. Expression of odd-paired like (opl), whichencodes a zinc-finger protein related to the Drosophilapair-ruled gene odd-paired, marks the future telencephalonwhile forkhead-5 (fkh5) expression designates the futurediencephalon (the next-most rostral region). The orthologuesof these two genes appear to play similar roles in anteriorCNS patterning of the Xenopus embryo but specificationtakes place earlier in the zebrafish. Assays with animal capexplants indicate that an endoderm-produced factor, cer-berus, first identified several years ago as a ‘‘head inducer’’ inXenopus, has opl-inducing activity. This observation indicatesa specific role for the anterior visceral endoderm (VE) ininduction of anterior CNS structures.

Such involvement of VE in induction of anterior CNSstructures is a relatively new area of investigation but severalother talks touched on it. A. Simeone (IIGB, Naples)reviewed data from mouse embryo experiments on the role ofanother essential gene for forebrain development, Otx-2,whose activity had previously been shown to be necessaryfor normal forebrain development. His results show that Otx-2must first be expressed in anterior VE, which underlies thefuture anterior forebrain area, to initiate specification of theanterior CNS; its subsequent expression in the anteriorneuroectoderm is required to maintain anterior forebraindevelopment. R. Beddington (NIMR, Mill Hill) describedsimilar roles for the unrelated transcription factor gene Hesx1in the mouse embryo. Its initial action in forebrain inductionmay also involve activation of cerberus synthesis, thoughperhaps indirectly. Another aspect of this early patterninginvolves a different diffusible protein factor. D. Kesslerdescribed findings in Xenopus that indicate that one effect ofthe organizer-expressed homeobox gene goosecoid is torepress Xwnt8 in the anterior region, thereby allowing headdevelopment. J. McGhee (U. of Calgary) described resultsin C. elegans, also implicating Wnt pathways in a-p develop-ment. His data show that development of the anterior portionof the gut specifically requires the Wnt pathway.

Patterning along the dorso-ventral (d-v) axis is, of course,equally important in embryonic development. Both Kessler’stalk and that of P. Lemaire (Marseilles-Luminy) describedthe molecular biology of the organizer region of the Xenopusembryo and the key, early role of the transcription factor genesiamois, expressed there, in establishing d-v polarity. Severaltalks dealt with d-v patterning in the development of neuralsystems. N. Papalopulu (Wellcome/CRC Institute, Cam-

bridge) described the activity of the winged helix transcriptionfactor XBF-1 in neurogenesis in the Xenopus embryo, whosedomain of expression helps position areas of neural differen-tiation along both the a-p and d-v axes. The d-v patterningaffect is seen in mis-expression experiments: induced lowlevels of expression of XBF-1 in the posterior neural plateexpands the area of neural differentiation both laterally andventrally. S. Wilson (University College London), investigat-ing the regulation of the zebrafish gene floating head (flh),finds that the flh boundary is delimited rostrally, along the a-pboundary, by the gene masterblind. Along the d-v axis,however, flh activity is set by a narrow range of intermediateconcentrations of bone morphogenetic protein-2 (BMP-2), amember of the TGF-B family. A somewhat similar phenom-enon in the Drosophila embryo was reported by S. Roth(Tubingen). He described the gene brinker (brk). brk isrequired for development of the neurogenic region in thisembryo, a region that lies immediately dorsal of the mesoderm-generating region, and acts by antagonizing the decapentaple-gic (dpp) signal transduction pathway; the resulting intermedi-ate range of dpp activities permits development of theneurogenic region. dpp is, like bmp-2, a member of theTGF-B gene family.

The theme of ‘‘multiple use’’ of particular gene products forvery different developmental roles is also well illustrated bydpp. A. Spradling (Carnegie Institute), in describing what isknown about oocyte stem cells in Drosophila, reported therecent finding that dpp is necessary for maintenance ofoocyte stem and controls their division rate.

A second signal transduction pathway that comes into playlater in oogenesis is that of the EGF pathway, which operatesthrough the EGF receptor (EGFR); it plays an essential role incorrect d-v patterning of the developing oocyte. N. Perri-mon (Harvard) described KEK-1, a transmembrane proteinthat inhibits EGFR activity. Overexpression of KEK-1 duringoogenesis ventralizes eggs while loss of KEK-1 activitycauses the reverse, dorsalization. The role of another gene,hold-up (hup), including its interaction with EGFR, in d-vdevelopment in late-stage Drosophila oocytes was describedby C. Malva (IIGB). The theme of multiple use-for-differentdevelopmental ends is further illustrated by the developmentof the tracheal system in Drosophila. Tracheal developmentemploys both the EGF and DPP pathways. B. Shilo (Weiz-mann Institute) presented data showing that the EGFRpathway is required for horizontal (a-p) branching of thetrachea while DPP is required for d-v growth of the trachealsystem. In addition, migration of the tracheal cells requiresexpression of another receptor gene (breathless), homolo-gous to the FGF receptor of mammals, implicating a possiblethird signalling transduction pathway.

The general structure of pathways was the implicit subjectof many of the talks of the conference. G. Rubin (UC,Berkeley) addressed it explicitly in describing new methods

Meetings

BioEssays 21.3 261

designed to fill out the details of gene interaction in thedevelopment of the Drosophila eye. He emphasized thatmost schematic diagrams of developmental pathways arejust fragments of the underlying reality; developmental pro-cesses really consist of linked networks of gene-controlledsteps with temporal aspects that are often not captured insingle, schematized diagrams.

A subset of the talks dealt explicitly with the final steps ofdevelopment in neural development, the differentiation ofcells and final states. T. Kidd (UC, Berkeley) described threegenes whose products are required for construction of theladder-like pattern of fascicles in the Drosophila embryonicCNS. roundabout (robo) encodes a transmembrane receptorprotein, whose activity is required to prevent axons fromcrossing the midline of the embryo; the slit gene encodes alarge secreted protein that acts as the ligand for robo, and;commissureless (comm) acts to downregulate robo, by some

form of post-translational regulation, at the midline, to allowaxons to cross the midline.

The ultimate neural ‘‘phenotype’’, of course, is be-havior. C. Bargmann (UCSF) described some of themolecular biology underlying olfactory reception in C. el-egans. Of the 19,000 genes contained in the genome ofthis animal, perhaps as many as 1000 encode specificolfactory receptor molecules. One of these is the receptorfor neuropeptide Y, a molecule implicated in appetite con-trol and feeding behavior in mammals. In nematodes, thereis a genetic polymorphism in this gene that determineschoice of two modes of behavior, social vs solitary, of theanimal. A specific single base pair change in the gene, inhomozygotes, produces the solitary form of behavior. Of themany instances of conserved molecules and functions de-scribed at the conference, this was, perhaps, the mostdramatic.

Meetings

262 BioEssays 21.3