The 2012 Thomas Hunt Morgan Medal Kathryn V. Anderson - Genetics

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The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt. Morgan Medal recognizes ...
THE 2012 GSA HONORS AND AWAR DS

The 2012 Thomas Hunt Morgan Medal Kathryn V. Anderson

The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics over the past 31 years. The George W. Beadle Medal recognizes distinguished service to the field of genetics and the community of geneticists. The Elizabeth W. Jones Award for Excellence in Education recognizes individuals or groups who have had a significant, sustained impact on genetics education at any level, from kindergarten through graduate school and beyond. The Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in solving significant problems in biological research through the application of genetic methods. We are pleased to announce the 2012 awards.

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T is a pleasure to congratulate Kathryn Anderson on her selection as the recipient of the 2012 Thomas Hunt Morgan Medal from the Genetics Society of America. Kathryn was chosen as this year’s recipient because of her career-long record of using elegant unbiased genetic screening and mutant/transgenic analysis to attack and solve important questions in developmental genetics. She is best known for three areas of work.

The genetics of early embryogenesis in Drosophila Kathryn began her studies of genes that regulate development when she was a graduate student with Judy Lengyel at the University of California at Los Angeles. Her graduate work established that the early Drosophila embryo’s development is largely under the control of maternally provided products, with a switchover to largely zygotic control after 2 hr of development (Anderson and Lengyel 1980). Subsequently, as a postdoc with Christiane Nüsslein-Volhard at the Max Planck Institut at Tübingen, and then continuing as an independent investigator at the University of California, Berkeley, Kathryn uncovered and dissected the maternal protein cascade that determines the dorsoventral polarity of the Drosophila embryo (e.g., Anderson and Nüsslein-Volhard 1984; reviewed in Morisato and Anderson 1995). Kathryn and her lab made numerous groundbreaking advances, of which a few are enumerated here. She showed that Toll was an important mediator of dorsoventral polarity (Anderson et al. 1985b) and that a ventral side developed locally, where Copyright © 2012 by the Genetics Society of America doi: 10.1534/genetics.112.139030

Toll was active (Anderson et al. 1985a). Her lab then reported that Toll was a membrane protein that resembled a class of transmembrane receptors that included the interleukin-1 receptor (Hashimoto et al. 1988). This finding was quite surprising, given that Toll was active in regulating an embryo enclosed in an eggshell without any obvious cells signaling to it! As is characteristic of Kathryn’s work, however, every possible alternative had been checked and eliminated, and there was no question that her iconoclastic finding was correct. To uncover what activated this receptor, Kathryn’s lab was a major contributor in determining the cascade of maternal dorsoventral (D/V) genes, sorting them into those that acted up- or downstream of Toll. Among the upstream genes, Kathryn’s lab identified members of a protease cascade (e.g., Chasan et al. 1992; reviewed in Hecht and Anderson 1992) present in the perivitelline space outside the egg’s plasma membrane and, through meticulous genetic analysis, identified the ultimate, maternally provided target of that cascade as the product of the spätzle gene (Schneider et al. 1994). The genetic and biochemical experiments of Kathryn’s lab showed that spätzle was the ligand for Toll. In separate experiments, her lab showed that the BMP-family member dpp acted zygotically, after the maternal cascade, as a morphogen to determine dorsality (Ferguson and Anderson 1992). Kathryn’s articles are classics, distinguished not only by their importance but also by the elegance of their genetic analysis—in experimental design, compelling results, and incisive interpretation; they are wonderful exemplars for students, for example, and many textbooks devote large parts of chapters to work from her lab.

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The genetics of the Toll pathway in immunity It turned out that Toll had a role beyond D/V determination— a role more consistent with its membership in the interleukin-1 receptor family: Toll is an important receptor in the immunity cascade in Drosophila (reviewed in Anderson 2000). The genetic analysis of the Toll pathway in the fly embryo laid the foundation for identifying and characterizing the roles of Toll-like receptors in innate immunity in mammals. Kathryn applied the genetic tools that she had developed for the analysis of D/V patterning to dissect the pathways in which Toll functioned to transduce immunity signals, working them out in detail by systematic genetic screens. Her work uncovered unanticipated and important players in the immunity cascade, including the identification of a peptidoglycan recognition protein as a key activator of antimicrobial peptide responses (Choe et al. 2002).

The genetics of early embryogenesis in mice About 15 years ago, first at the University of California at Berkeley and then at Sloan-Kettering, Kathryn courageously began an entirely new project. She chose to apply to the mouse the same type of unbiased genetic screening that had been so powerful in identifying new genes and cascades in Drosophila development (Kasarskis et al. 1998). Although of undisputed importance, such a screen was clearly going to take a long time to pay off. Recognizing that such a screen was, nevertheless, essential for a true understanding of the genes that controlled mouse embryogenesis, Kathryn began by doing a sabbatical with Rosa Beddington to begin to learn mouse embryology. Then, in her own lab, she forged ahead with the same experimental care, rigor, and creative experimental design that characterized her fly work. Kathryn is one of the few established fly researchers to make a complete transition to the mouse. Her screen has generated .130 mutants that affect the mid-gestational mouse embryo, and Kathryn and her collaborators have molecularly identified the mutant lesions in nearly 90 of these genes. These mutants allow delineation of pathways by which the mouse embryo’s body axes are established or that regulate morphogenesis, topics that resonate with Kathryn’s earlier work on Drosophila embryos. Results of Kathryn’s unbiased screens have led to the identification of morphogenesis regulators at many biological levels, including transcription, actin branching, vesicle transport, and collective cell migration (to name just a few; e.g., see Eggenschwiler et al. 2001; Merrill et al. 2004; Rakeman and Anderson 2006; Migeotte et al. 2011). The discoveries have taken the field into new directions or connected known pathways or phenomena in previously unanticipated ways. For example, results from Kathryn’s screens revealed an unanticipated essential role of cilia in hedgehog signaling during early mouse embryogenesis. Because two of the genes identified in the screens had homologs that are important in intraflagellar transport in Chlamydo-

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monas, Kathryn examined cilia in the mutant embryos (Huangfu et al. 2003). She found that cilia were absent from the node in the mutants. Given the role of cilia in setting up left/right (L/R) polarity, loss of cilia from the node would be expected to cause L/R patterning defects, and Kathryn’s lab observed just such effects in the mutants. Kathryn’s careful phenotyping showed that the same mutants’ neural defects also resembled those of SHH mutants. This led her to make the leap to test the relationship of hedgehog pathway members to cilia. Kathryn and her lab showed that hedgehog pathway components are localized to, or enriched in, cilia and that hedgehog signaling itself can affect this localization. From there, she and her lab branched out to dissect node assembly, ciliary assembly and intracilia transport, the hedgehog pathway’s role in development, and disease-associated genes that affect ciliary structure or formation (e.g., Caspary et al. 2007; Tuson et al. 2011), while continuing to dissect other pathways that regulate morphogenesis and patterning of the body. Kathryn is a developmental-geneticist’s geneticist. From first principles, she designs and does rigorous large-scale unbiased screens for the genes that regulate important developmental processes. Her great attention to detail, sophisticated genetic manipulations (every type of epistasis, molecular genetic design, etc.), and creative genetic and molecular thought has repeatedly led to major, important, and unanticipated discoveries of new developmental and biological principles. And she has done this in two model organisms. In addition to her major scientific contributions, Kathryn is a collaborative and supportive scientist who generously shares reagents and mutants with the community. She works quietly, but the importance and quality of her work speaks for itself and has already led to several recognitions, including Kathryn’s election as a Fellow of the National Academy of Sciences, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences. Kathryn modestly credits her mentors, all outstanding women scientists, with helping her succeed. She, in turn, has trained and mentored many geneticists who themselves have gone on to make major contributions to the fly and mouse fields. We are delighted that the Genetics Society of America has chosen to recognize, with this medal, Kathryn’s career-long record of important and precedent-setting discoveries based on elegant genetics.

Literature Cited Anderson, K. V., 2000 Toll signaling pathways in the innate immune response. Curr. Opin. Immunol. 12: 13–19. Anderson, K. V., and J. A. Lengyel, 1980 Changing rates of histone mRNA synthesis and turnover in Drosophila embryos. Cell 21: 717–727. Anderson, K. V., and C. Nüsslein-Volhard, 1984 Information for the dorsal–ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 311: 223–227. Anderson, K. V., L. Bokla, and C. Nüsslein-Volhard, 1985a Establishment of dorsal-ventral polarity in the Drosophila embryo:

the induction of polarity by the Toll gene product. Cell 42: 791–798. Anderson, K. V., G. Jurgens, and C. Nüsslein-Volhard, 1985b Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42: 779–789. Caspary, T., C. E. Larkins, and K. V. Anderson, 2007 The graded response to Sonic Hedgehog depends on cilia architecture. Dev. Cell 12: 767–778. Chasan, R., Y. Jin, and K. V. Anderson, 1992 Activation of the easter zymogen is regulated by five other genes to define dorsal-ventral polarity in the Drosophila embryo. Development 115: 607–616. Choe, K. M., T. Werner, S. Stoven, D. Hultmark, and K. V. Anderson, 2002 Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 296: 359–362. Eggenschwiler, J. T., E. Espinoza, and K. V. Anderson, 2001 Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412: 194–198. Ferguson, E. L., and K. V. Anderson, 1992 Decapentaplegic acts as a morphogen to organize dorsal-ventral pattern in the Drosophila embryo. Cell 71: 451–461. Hashimoto, C., K. L. Hudson, and K. V. Anderson, 1988 The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52: 269–279. Hecht, P. M., and K. V. Anderson, 1992 Extracellular proteases and embryonic pattern formation. Trends Cell Biol. 2: 197–202.

Huangfu, D., A. Liu, A. S. Rakeman, N. S. Murcia, L. Niswander et al., 2003 Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426: 83–87. Kasarskis, A., K. Manova, and K. V. Anderson, 1998 A phenotypebased screen for embryonic lethal mutations in the mouse. Proc. Natl. Acad. Sci. USA 95: 7485–7490. Merrill, B. J., H. A. Pasolli, L. Polak, M. Rendl, M. J. Garcia-Garcia et al., 2004 Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131: 263–274. Migeotte, I., T. Omelchenko, A. Hall, and K. V. Anderson, 2011 Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse. PLoS Biol. 8: e1000442. Morisato, D., and K. V. Anderson, 1995 Signaling pathways that establish the dorsal-ventral pattern of the Drosophila embryo. Annu. Rev. Genet. 29: 371–399. Rakeman, A. S., and K. V. Anderson, 2006 Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching. Development 133: 3075–3083. Schneider, D. S., Y. Jin, D. Morisato, and K. V. Anderson, 1994 A processed form of the Spätzle protein defines dorsal-ventral polarity in the Drosophila embryo. Development 120: 1243–1250. Tuson, M., M. He, and K. V. Anderson, 2011 Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138: 4921–4930.

Mariana F. Wolfner and Tim Schedl

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