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Copyright 0 1994 by the Genetics Society of America Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove A Century of Homeosis, A Decade of Homeoboxes William McGinnis Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114 NE hundred years ago, while the science of genet- ing mammals, and were proposed to encode DNA- 0 ics still existed only in the yellowing reprints of a binding homeodomainsbecause of a faint resemblance recently deceased Moravian abbot, WILLIAMBATESON to mating-type transcriptional regulatory proteins of (1894) coined the term homeosis to define a class of budding yeast and an even fainter resemblance to bac- biological variations in whichone elementof a segmen- terial helix-turn-helix transcriptional regulators. tally repeated array of organismal structures is trans- The initial stream of papers was a prelude to a flood formed toward the identity of another. After the redis- concerning homeobox genes and homeodomain pro- coveryof MENDEL’Sgenetic principles, BATESONand teins, a flood that has channeled into a steady river of others (reviewed in BATESON1909) realized that some homeo-publications, fed by many tributaries. A major examples of homeosis in floral organs and animal skel- reason for the continuing flow of studies is that many etons could be attributed to variation in genes. Soon groups, working on disparate lines of research, have thereafter, as the discipline of Drosophila genetics was found themselves swept up in the currents when they born and was evolving into a formidable intellectual found that their favorite protein contained one of the force enriching many biologicalsubjects, it gradually be- many subtypes of homeodomain. This was in part be- came clear that fruitflies contained multiple “homeotic” cause the definition of what proteins belonged to the genes (e.g., bithorax,aristapedia and proboscipedia) homeodomain family expanded to include proteins that (BRIDGESand MORGAN1923; BALKASCHINA 1929;BRIDGES had only marginal amounts of sequence similarity to the and DOBZHANSKY1933), some of which appeared to be founder members in the Drosophila Antennapedia and loosely clustered on the third chromosome. These ge- Bithorax gene complexes. Many of the proteins that netic studies culminated in the systematic analyses of have homeodomains have nothing todo with BATESON’S LEWIS(1978) and KAUFMAN et al. (1980),which provided version of homeosis, although there is a loosely defined preliminary definitions of the many homeotic genes of structural subgroup of homeodomains that is closely the Bithorax and Antennapedia complexes, and also linked to homeotic genetic functions in animals. showed that the mutant phenotypes for most of these The initial stream of reports immediately explained genes could be traced back to patterning defects in the (or purported to explain) some of the burning ques- embryonic body plan. tions concerning homeotic genes. They seemed to be a Ten years ago, a sudden stream of papers (MCGINNIS fairly closely conserved gene family, and the sequence et al., 1984a,b,c; SCOTTand WEINER1984; LAUGHON and that validated their family membership, the homeobox, SCOTT1984; SHEPHERDet al. 1984; CARRASCO et al. 1984; provided a plausible biochemical function for their ac- LEVINEet al. 1984) introduced the homeobox to devel- tion. They were likelyto be DNA-binding transcriptional opmental genetics and sketched its basic outlines. In regulators that would modulate the expression of many retrospect, each of these studies contained relatively few downstream genes. The conservation of very similar ho- data for theimpact they had. Putting thebest face on it, meobox sequences in other animals suggested that one could claim they are reports of exemplary brevity. homeotic-like genetic functions might exist in structur- These reports defined homeoboxes as members of a ally homologous genes other than in Drosophila. That highly conserved familyof DNA sequences that ap is, perhaps a conservation of developmental genetic cir- peared to be preferentially associated with homeotic cuitry could be detected at themolecular level that was and segmentation genes of Drosophila. Homeobox se- invisible at the level of comparative embryological mor- quences were highlyconserved in other animals, includ- phology. All of these things had been suggested before Genetics 137: 607-611 uuly, 1994) 608 W. McCinnis in either explicit or vague terms by those with insight, to clone genes. This was especially true in Drosophila, prescience, and/or theoretical leanings (WOLPERT 1969; which already had a mother lode of genetic and cyto- GARCIA-BELLIDO 1977; GARCIA-BELLIDOet al. 1979; LEWIS genetic studies as a biological treasure. And this rich 1978; RAFF and KAUFMAN 1983), but a bit of molecular lode ofgenetics was indeed minedfor all it was worth by evidence goes a long way toward swaying opinion (e+ anyone with a homeobox probeand a hypothesis (e.g., pecially the opinion of molecular biologists), so that FJOSEet al. 1985; LEVINEet al. 1985; REGULSKI et al. 1985; much was made of the homeobox discovery. MACDONALD et al. 1986).For those of us who weredoing In the original set of reports, the evidence for any of something with homeoboxes as students or postdocs the conclusions was incomplete at best, which did not with WALTER GEHRINGin Basel, Switzerland (which in- prevent the original authors from discussing them as cluded MICHAELLEVINE, ATSUSHIKUROIWA, ERNST HAFEN, quite likely to be true. There was even more hope ex- ANDERS FJOSE,MAREK MLODZIK,and me),it will be difficult pressed (and a bit of metaphorical hyperbole, at least in to forget the feeling of guiltypleasure when we realized the titles) in a variety of review articles that suggested how incredibly easy it might be to clone andidentify the variously thatthe homeobox might be a biological coding regions of the Drosophila homeotic genes and equivalent of the Rosetta stone, theuniversal genetic key many of the segmentation genes. That this suspicion to body plan, and so on (e.g.,STRUHL 1984; SLACK1984). wasn’t entirely a Swiss chocolate-inspired delusion was There were even articles in newspapers and popular fortified by a chanceconversation with GINESMORATA at magazines announcing that something important had a Swiss-USGEB meeting. Some of us, in collaboration happened in developmental biology that might be rel- with FRANCOIS mCHand WELCOMEBENDER, had found evant even to those sophisticated mammals that perform only three homeoboxes in Bithorax complex DNA a daily perusal of The New York Times. All of this at- (REGULSKI et al., 1985). At the time, the number of tention jump-started homeobox gene research in Dro- proteincoding transcription units in the Bithorax com- sophila, where it would be defined and enrichedbeyond plex was thought to be eight or more, but MORATA, anyone’s wildest dreams by the rich genetics of that ani- ERNESTO SANCHEZ-HERRERO,and their co-workers hadjust mal. But perhaps themost hope, and themost rapid and discovered that the Bithorax complex contained only concerted jump outof the homeobox research starting three lethal complementationgroups (SANCHEZ- gate, occurred in laboratories studying development in HERREROet al. 1985),suggesting correctly that the three those vertebrates that had a rich history of descriptive bithorax homeoboxes corresponded to those three le- and experimentalembryology, but rudimentary genetic thal genes, now known as Ubx, abd-A and Abd-B. tool kits compared with Drosophila. Herethe ho- One of the most exciting outcomes of the early ho- meobox seemed to provide a toehold halfway up what meobox research in Drosophila was the general way it had seemed to be a slippery and impassable barrier of confirmed some of E. B. LEWIS’Sspeculations about the developmental genetics. evolution of the Bithorax complex. In an article that is Not all concurred with the blinkered enthusiasm over oft cited but rarely read in its complex entirety, LEWIS the meaning and utility of the homeobox homology. (1978) proposed that the Bithorax complex genes were Some fancifully suggested that many developmental bi- members of a gene family, having duplicated and di- ologists were inthe gripof “homeobox madness” or “ho- verged from a common ancestor and in the process hav- meobox fever” (RAFF and RAFF 1985; ROBERTSON1985; ing acquired divergent functions that accounted for WILKINS1986), apparently a horizontally transmitted dis- some of the morphological differences that distinguish ease that caused a loss of one’s critical faculties. Some the Drosophila body plan from that of more primitive geneticists and evolutionary biologists were thought to arthropods. Luckily for some of us,LEWIS put thatspecu- be immune to this syndrome. Many of those with cool lation in the first paragraph instead of in the middle of heads who read theoriginal homeobox papers carefully, the article among the terse and tortuous genetics. T. C. and interpreted them critically, found some of the ar- KAUFMAN (RAFF and KAUFMAN 1983) had also proposed an guments specious. And some were, if the results within extension of this to embrace the homeotic genes of the a particular paper are considered in isolation. In those Antennapedia complex controlling head and thoracic days, however,the results were coming along so fast that development. It is still unclear how much the variation by the time one paper was written, the results for the next, in homeotic protein function
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