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Jaws of the Fates

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Science  11 Oct 2002:
Vol. 298, Issue 5592, pp. 371-373
DOI: 10.1126/science.1077706

In his poem about the lonely “Maldive Shark,” [HN1] Herman Melville describes the daunting jaws of a serious meat-eater, which serve as an asylum for the sleek little pilot fish [HN2], azure and slim, hiding in his “jaws of the Fates.” The “jaws of the Fates” may act rather unpredictably in the uncharted oblivion of the Indian Ocean, but Depew et al. [HN3] (1) report a remarkable catch—the genes that dictate the fates of jaws—on page 381 of this issue. These authors turn lower jaws into upper jaws by simultaneously inactivating the homeobox genes Dlx5 and Dlx6 [HN4] of mice. Such a spectacular transformation of “jaw identity” unveils a family of genes that are crucial for directing formation of the vertebrate face. This gene family may have been subject to profound modifications during vertebrate evolution and in certain human congenital diseases [HN5]. The Dlx5 and Dlx6 genes are now implicated in the elaboration of vertebrate lower jaws, from the ferocious feeding machinery of the great white shark to the sophisticated hearing system of mammals.

A complex series of cellular and molecular interactions underlies the assembly of the vertebrate face [HN6]. Most structures are formed by the neural crest [HN7], a tissue that emanates from the early embryonic brain and populates the so-called branchial arches [HN8] (2). Branchial arches are a segmental series of bulges in the embryonic head and are predecessors of all facial elements. Within the first (mandibular) branchial arch, jaw elements develop from three bulges: the mandibular, maxillary, and frontonasal processes that are filled by neural crest cells from different origins (midbrain and hindbrain) (3). Widespread mixing between them supports the notion that jaw neural crest is exposed to instructive signals from its environment that establish a proximodistal axis [HN9] to the jaw-forming branchial arch (3). Such external cues are translated into a code of neural crest proximodistal “identity,” leading to the precisely orchestrated formation of skeletal and muscular elements. Much evidence implicates the Hox homeobox genes [HN10] as the encoders of “rostrocaudal identity” in all branchial arches posterior to the jaw-forming arch. However, until now no genes have been proven to act as true selector genes for proximodistal identity of neural crest cells in branchial arches.

A more symmetrical smile.

(A) Skeleton of the head of a jawed vertebrate, Acanthodes, showing symmetry between upper and lower jaw elements (green) and hyoid elements (yellow). The upper jaw (palatoquadrate) and lower jaw are both subdivided in two by a cartilaginous bridge. (B) Jaws of the acanthodian Poracanthodes with symmetrical jaws and dentition (yellow). The success of jawed vertebrates is partly attributable to the morphological independence (that is, asymmetry) of upper and lower jaws encoded by differentially expressed Dlx genes. Elaboration of this developmental code imbued vertebrates with hearing machinery and a wide variety of feeding capabilities. [Adapted from (8)]

CREDIT: KATHARINE SUTLIFF/SCIENCE

Jawed vertebrates have three pairs of Dlx homeobox genes—Dlx1/2, Dlx5/6, and Dlx3/7—that are expressed in restricted domains across the proximodistal axis of the branchial arches (4). Their nested expression within the branchial arches and the fact that their Drosophila homolog distalless [HN11] is a master regulator of distal leg identity make the Dlx genes excellent candidates for encoding distal identity in vertebrates. In all bilateral organisms, distalless genes appear to be involved in controlling the outgrowth of body appendages (5). Thus, the idea that the vertebrate Dlx homologs serve a similar function is attractive. Rather disappointingly, mice missing a single Dlx gene exhibit only piecemeal changes in the identities of isolated skeletal elements and teeth. This finding suggested that Dlx genes act as “micromanagers” rather than as “master regulators.” Now, Depew and colleagues report the striking phenotype of the Dlx5/6 double mutant mouse [HN12] (1). They provide evidence that Dlx5 and Dlx6 are indeed the selectors of distal branchial arch identity. Their work suggests that the absence of a clear phenotype in mice lacking one Dlx gene is due to compensation by other coexpressed Dlx genes. Thanks to their discovery, the concept of a proximodistal molecular identity code is alive and well.

The phenotype of the Dlx5/6 double mutant mouse is complex but remarkably clearcut. All of the skeletal elements below the primary jaw joint (the joint between the malleus and incus of the mammalian middle ear [HN13]) are missing. Even more intriguing, in the region of the lower jaw, the mutant mice possessed a second complete set of bona fide upper jaw elements. During the early evolution of mammals, the major upper jaw element (the so-called palatoquadrate) became fragmented. Parts of the palatoquadrate became fused to the braincase—the “tennis racket”-shaped alisphenoid bone in figure 3E and supplementary figure 3D of the Depew et al. paper—or gave rise to elements of the mammalian pharynx (pterygoid). Other parts such as the quadrate turned into the mammalian incus, and the hyomandibula became the third middle ear bone (the stapes)—all elements of a new hearing apparatus (6). [HN14] In the Dlx5/6 double mutant mice all of these elements are duplicated, resulting in a symmetrical instead of an asymmetrical mouth.

If Dlx5 and Dlx6 are distal selector genes, then where does the initial patterning information for the branchial arch proximodistal axis come from? A recent elegant paper by Couly et al. [HN15] sheds light on this difficult question (7). By transplanting pharyngeal endoderm [HN16] into different locations in the developing chick head, Couly et al. generated jaw duplications that are remarkably similar to those obtained by Depew et al. (1). A growing body of evidence suggests that initial cues from the pharyngeal endoderm impose a first proximodistal patterning axis onto the adjacent branchial arch neural crest cells. This prepattern is then “interpreted” by neural crest cells, resulting in the nested expression of Dlx gene pairs, Dlx5/6 and Dlx3/7, by these cells. If this is the case, what does the Dlx5/6 mutant phenotype tell us about the evolution of jaws?

Although upper and lower jaw elements have never been completely symmetrical during vertebrate history, early jawed vertebrates related to the ancestors of bony fish (such as acanthodians [HN17]) experimented with the shape and symmetry of their jaws. Acanthodians, for example, sometimes displayed remarkable symmetry between their upper and lower jaw elements (see the figure, part A, green) as well as in their dentition (see the figure, part B, yellow) (8). Such symmetrical features, which disappeared later in evolutionary history, now reappear in the Dlx5/Dlx6 double mutant mice.

The Depew et al. work suggests that lower jaw patterning that is dependent on Dlx5/6 expression may have been elaborated and embellished between the phylogenetic nodes of jawed vertebrate and bony fish ancestors. Going back one step further in evolutionary history, jawless vertebrates such as lampreys [HN18] only have four Dlx genes with unclear homologies to their jawed vertebrate counterparts (9). All lamprey Dlx genes are expressed in branchial arches, but a nested expression pattern appears to be the invention of the jawed vertebrates (10). Our knowledge of the enhancer organization that controls this nested Dlx gene expression in jawed vertebrates is still rudimentary. Comparative genomic and functional studies of the regulatory elements controlling Dlx gene expression in lampreys, sharks, bony fish, coelacanths, and tetrapods will reveal the molecular evolution of the proximodistal code that underlies the shapes and fates of jaws.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is available on CancerWEB.

The Life Sciences Dictionary is provided by the BioTech Web site of the University of Texas Institute for Cellular and Molecular Biology.

The xrefer Web site provides scientific dictionaries and other reference works.

A Database of Embryological Terms is provided by M. Cavey, Department of Biological Sciences, University of Calgary, for an embryology course.

Web Collections, References, and Resource Lists

Biology Links are provided by the Department of Molecular and Cellular Biology, Harvard University.

The Google Web Directory provides links to Internet resources related to developmental biology.

The Virtual Library-Developmental Biology is provided by the Society for Developmental Biology.

The WWW Virtual Library of Cell Biology includes sections of Internet links for gene expression and cellular aspects of development.

W. Wasserman, Department of Biology, Loyola University of Chicago, provides a resource page on developmental biology.

Developmental Biology Online is a supplemental education resource provided by S. Scadding, Department of Zoology, University of Guelph, Canada. Included are links to Internet resources on developmental biology and cell biology and a glossary. Definitions of terms for direction and orientation are provided.

Online Texts and Lecture Notes

J. Kimball provides Kimball's Biology Pages, an online biology textbook. Three articles on embryonic development are included.

Embryo Images is a tutorial on mammalian development using scanning electron micrographs provided by the School of Medicine, University of North Carolina.

The UNSW Embryology Web site is an educational resource on embryological development provided by M. Hill, School of Anatomy, University of New South Wales, Australia.

Virtual Embryo/Dynamic Development is a Web resource provided by L. Browder, Department of Biochemistry and Molecular Biology, University of Calgary.

A Web supplement to the sixth edition of the textbook Developmental Biology is provided by the author S. Gilbert, Department of Biology, Swarthmore College, PA. Additional supplemental material is provided on Gilbert's Zygote Web site.

J. Armbruster, Department of Biological Sciences, Auburn University, provides lecture notes for a course on vertebrate comparative anatomy.

L. Zwiebel and L. Solnica-Krezel, Department of Biological Sciences, Vanderbilt University, provide lecture notes for a developmental biology course.

L. Sweeney, Department of Biology, Bryn Mawr College, PA, offers lecture notes for a developmental biology course.

G. Podgorski, Department of Biology, Utah State University, offers lecture notes for a course on developmental biology.

D. Linden, Biology Department, Occidental College, Los Angeles, offers lecture notes for a course in developmental cell biology.

W. Powell, Biology Department, Kenyon College, OH, provides lecture notes for a course on genetics and development.

C. Kimmel, Department of Biology, University of Oregon, offers lecture notes for a course on vertebrate evolution and development.

D. Rand, Program in Ecology and Evolutionary Biology, Brown University, offers lecture notes for a course on evolutionary biology.

General Reports and Articles

Developmental Dynamics, the journal of the American Association of Anatomists, makes available an online collection of review articles.

The Atlas of Genetics and Cytogenetics in Oncology and Haematology offers a presentation by J. Bonaventure titled “Skeletal development in human: A model for the study of developmental genes.”

The 4 July 1997 issue of Science had a news article by E. Pennisi and W. Roush titled “Developing a new view of evolution.” The 25 June 1999 issue had a review by A. H. Knoll and S. B. Carroll titled “Early animal evolution: Emerging views from comparative biology and geology.”

The May 1997 issue of the Proceedings of the National Academy of Sciences had an article by G. Panganiban et al. titled “The origin and evolution of animal appendages” (5). The 25 April 2000 issue had a special feature on evolutionary developmental biology with perspective and review articles as well as topical research articles.

Numbered Hypernotes

1. Herman Melville's poem “The Maldive Shark” is available in the Poetry Archive. D. Campbell, Department of English, Gonzaga University, provides a resource page about Melville.

2. Sharks and pilot fish. A photograph by E. Robinson of a shark with pilot fish is provided on the ScubaDuba Web site. An entry for pilot fish is included in xrefer's Oxford Paperback Encyclopedia. FishBase has an entry for Naucrates ductor (pilot fish). The NOAA Photo Library displays a 19th-century etching of a pilot fish. EnchantedLearning.com offers an educational presentation about sharks. The Ichthyology Department of the Florida Museum of Natural History offers a resource page on sharks. Fiona's Shark Mania Web site provides links to Internet resources on sharks.

3. M. J. Depew and J. L. R. Rubenstein are in the Neuroscience Graduate Program and the Department of Psychiatry, University of California, San Francisco; the Rubenstein Lab has a Web page. T Lufkin is at the Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York.

4. Homeobox genes Dlx5 and Dlx6. Homeobox is defined in xrefer's Dictionary of Biology. SWISS-PROT has a keyword entry for homeobox. InterPro has an entry for the homeobox domain. S. Gilbert makes available a student presentation by K. Panfilio on the Dlx gene family prepared for a seminar on developmental genetics. C. Kimmel offers lecture notes on Dlx genes for a course on vertebrate evolution and development. The GeneCards database from the Weizmann Institute of Science has entries for Dlx5 and Dlx6 genes with links to other Internet resources provided. The Jackson Laboratory's Mouse Genome Informatics Web site has entries for the Dlx5 and Dlx6 genes of mice.

5. Congenital disorders possibly related to Dlx genes. Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders, has entries for members of the Dlx gene family: Dlx1, Dlx2, Dlx3, Dlx7 (Dlx4), Dlx5, and Dlx6.

6. Formation of the vertebrate face. Embryo Images has a section on craniofacial development. T. Marino, Department of Anatomy and Cell Biology, Temple University School of Medicine, provides a presentation on the development of the face as part of an embryology resource page. A student presentation on human facial development is made available on the anatomy resource page provided by the School of Biological Sciences, University of Manchester, UK. R. Tucker, University of California, Davis, Department of Cell Biology and Human Anatomy, provides lecture notes on the development of the head, neck, and face (parts one and two) for a course on developmental, gross, and radiologic anatomy.

7. Neural crest. M. Hill's UNSW Embryology offers a presentation on the neural crest. S. Gilbert makes available a student presentation by K. Panfilio on neural crest cells, which was prepared for a seminar on developmental genetics. D. O'Day, Department of Zoology, University of Toronto at Mississauga, provides lecture notes on the neural crest for a course on human development. A student project on the neural crest was prepared by K. Moran for a course on developmental biology offered by the School of Biological Sciences, University of Manchester. The October 1996 issue of Development had an article (full text available in PDF format) by G. Koentges and A. Lumsden titled “Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny” (3).

8. Branchial arches. Pharyngeal arch (branchial or visceral arch) is defined in xrefer's Concise Medical Dictionary. The 1918 edition of Gray's Anatomy of the Human Body, made available by Bartleby.com, has a section on the branchial region. The Gross Anatomy Homepage at Marshall University's School of Medicine makes available notes on the development of branchial arches for a course on medical gross anatomy. The Department of Anatomy, Howard University College of Medicine, makes available lecture notes on the branchial apparatus for an anatomical sciences course. T. Marino provides a presentation on pharyngeal (branchial arches) as part of an embryology resource page. P. Hunt, Department of Biological Sciences, University of Durham, UK, offers a research presentation on branchial arches.

9. Proximodistal and other axes of development. Distal and proximal are defined in the introduction to anatomy terminology provided by the Faculty of Medicine, University of Calgary School of Medicine. L. Solnica-Krezel defines proximodistal and other axes of developing limbs in lecture notes on limb development for a course on developmental biology. UNSW Embryology offers a presentation on the axes of limb molecular development with a section on proximal/distal patterning.

10. Hox homeobox genes. Kimball's Biology Pages includes a section on the Hox cluster of homeobox genes in the presentation titled “Embryonic development: Putting on the finishing touches.” UNSW Embryology offers a presentation on Hox homeobox genes in the section on molecular development and a presentation on the development of the rostrocaudal axis. L. Browder's Dynamic Development makes available a presentation by D. Rancourt titled “Establishment of spatial patterns of gene expression during early vertebrate development: Hox genes.” C. Kimmel provides lecture notes on Hox genes and anterior-posterior patterning for a course on vertebrate evolution and development. D. O'Day offers lecture notes on limb development and Hox genes for a course on human development. W. Powell provides lecture notes on Hox genes and molecular evolution for a course on genetics and development.

11. Drosophila homolog distalless. S. Gilbert's Zygote Web site includes a presentation on distalless. FlyBase offers a report on the gene Dll (distal-less). The Interactive Fly offers a presentation on Dll, including a section on evolutionary homologs.

12. Dlx5/6 double mutant mouse. The Jackson Laboratory's TBASE (Transgenic/Targeted Mutation Database) has an entry for the Dlx5/6 (-/-) mouse, as well as an April 2002 Knockout of the Month feature on this mouse with links to Internet resources.

13. Mammalian middle ear. An Anatomical Tour of the Ear includes a description of bones of the human middle ear. The vertebrates section of the Palaeos Web site provides an overview of the ear and a presentation on the incus. Promenade 'round the Cochlea, a tutorial on the human ear and auditory system, offers a presentation on the middle ear. Embryo Images has a Section on ear development. R. Tucker provides lecture notes on the development of the ear for a course on developmental, gross, and radiologic anatomy.

14. Evolution of the mammalian jaw and ear. Animal Diversity Web, a presentation of the University of Michigan Museum of Zoology, offers an article on mammalian jaws and ears. S. Carr, Department of Biology, Memorial University of Newfoundland, presents a graphic introduction to the evolution of the mammalian jaw in lecture notes on systematics for a course on the principles of evolution and systematics. Evolution of the mammalian jaw and ear is discussed in an article by M. Benton titled “Evidence of evolutionary transitions,” which is available on the Actionbioscience.org Web site. The 23 April 1999 issue of Science had a News Focus article by E. Pennisi titled “From embryos and fossils, new clues to vertebrate evolution” that discussed the origin of jaws. C. Kimmel offers lecture notes titled “Gills make jaws make ears” for a course on vertebrate evolution and development.

15. Couly et al. paper. The February 2002 issue of Development had an article by G. Couly, S. Creuzet, S. Bennaceur, C. Vincent, and N. M. Le Douarin (at the Institut d'Embryologie Cellulaire et Moléculaire du CNRS et du Collège de France) titled “Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head.”

16. Endoderm is defined in the BioTech Life Sciences Dictionary and in xrefer's Dictionary of Biology. Developmental Biology Online provides a presentation on the derivatives of endoderm. D. Linden offers lecture notes on the endoderm for a course in developmental cell biology.

17. Acanthodians. An entry for Acanthodii (acanthodians) is included in xrefer's Dictionary of Earth Sciences. The Palaeos Web site provides an introduction to Acanthodii. J. Armbruster includes a section on Acanthodii in lecture notes on fish for a course on vertebrate comparative anatomy.

18. Lampreys. The online Columbia Encyclopedia has an entry for lamprey. The University of California Museum of Paleontology offers an introduction to lampreys. The Tree of Life Web Project offers a presentation on lampreys. An information page on lampreys is provided by the SAREP Web site at the Department of Natural Resources, Cornell University. J. Armbruster includes a section on jawless fishes (including lampreys) in lecture notes for a course on vertebrate comparative anatomy. The 17 May 2002 issue of Science had a report by Y. Shigetani et al. titled “Heterotopic shift of epithelial-mesenchymal interactions in vertebrate jaw evolution” (10). The 13 February 2001 issue of the Proceedings of the National Academy of Sciences had an article by A. H. Neidert, V. Virupannavar, G. W. Hooker, and J. A. Langeland titled “Lamprey Dlx genes and early vertebrate evolution” (9).

19. G. Koentges and T. Matsuoka are at the Wolfson Institute of Biomedical Research, University College London.

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