Ed Laufer

Sonic hedgehog mediates the polarizing activity of the ZPA

The zone of polarizing activity (ZPA) is a region at the posterior margin of the limb bud that induces mirror-image duplications when grafted to the anterior of a second limb. We have isolated a vertebrate gene, Sonic hedgehog, related to the Drosophila segment polarity gene hedgehog, which is expressed specifically in the ZPA and in other regions of the embryo, that is capable of polarizing limbs in grafting experiments. Retinoic acid, which can convert anterior limb bud tissue into tissue with polarizing activity, concomitantly induces Sonic hedgehog expression in the anterior limb bud. Implanting cells that express Sonic hedgehog into anterior limb buds is sufficient to cause ZPA-like limb duplications. Like the ZPA, Sonic hedgehog expression leads to the activation of Hox genes. Sonic hedgehog thus appears to function as the signal for antero-posterior patterning in the limb.

Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud

Proper limb growth and patterning requires signals from the zone of polarizing activity in the posterior mesoderm and from the overlying apical ectodermal ridge (AER). Sonic hedgehog and Fgf-4, respectively, have recently been identified as candidates for these signals. We have dissected the roles of these secreted proteins in early limb development by ectopically regulating their activities in a number of surgical contexts. Our results indicate that Sonic hedgehog initiates expression of secondary signaling molecules, including Bmp-2 in the mesoderm and Fgf-4 in the ectoderm. The mesoderm requires ectodermally derived competence factors, which include Fgf-4, to activate target gene expression in response to Sonic hedgehog. The expression of Sonic hedgehog and Fgf-4 is coordinately regulated by a positive feedback loop operating between the posterior mesoderm and the overlying AER. Taken together, these data provide a basis for understanding the integration of growth and patterning in the developing limb.

Ectopic expression of Sonic hedgehog alters dorsal-ventral patterning of somites

Differentiation of somites into sclerotome, dermatome, and myotome is controlled by a complex set of inductive interactions. The ability of axial midline tissues, the notochord and floor plate, to induce sclerotome has been well documented and has led to models in which ventral somite identity is specified by signals derived from the notochord and floor plate. Herein, we provide evidence that Sonic hedgehog, a vertebrate homolog of the Drosophila segment polarity gene hedgehog, is a signal produced by the notochord and floor plate that directs ventral somite differentiation. Sonic hedgehog is expressed in ventral midline tissues at critical times during somite specification and has the ability, when ectopically expressed, to enhance the formation of sclerotome and antagonize the development of dermatome.

Evolution in developmental biology: of morphology and molecules.

Experimental embryologists, molecular biologists, evolutionary morphologists, paleontologists and most other modem practitioners of developmental biology met recendy (British Sodety for Developmental Biology Spring Meeting, Edinburgh, UK; organized by M. Akam, P. Holland and G. Wray) to discuss the evolution of development. Despite its broad purview, four unifying themes emerged from the meeting. First, similarities in molecular pathways in diverse organisms are revealing previously unappreciated levels of homology: the animals we study now seem more similar than we could possibly have anticipated. Second, comparisons of genetic pathways are leading to reevaluation of evolutionary relationships at all taxonomic levels. Third, the identification of patterns of variance and invariance at the levels of genome structure and gene expression are providing interesting insights into the evolution of developmental mechanisms. Finally, and perhaps most sisniflcanfly, data from a range of approaches from the paleontological through the morphological to the molecular are being integrated to give more complete images in a common biological language. Comparisons of gene expression patterns (primarily of the homeotic genes and gene encoding intercellular signalling molecules) are prompting reassessment of the relationships between body parts across members of different phyla. Structures which by morphological or paleontological criteria have not previously been considered homologous may in fact be related by common descent. Recent dam suggest that segmental (memmeric) boundaries along the body axis, as well as the limbs, gut, eyes and heart, and specification of muscle groups, may all be homologized from vertebrates to insects to nematodes. In general, these are regulatory homologies, reflecting common control mechanisms, and are not necessarily manifested in morphological details. Homeotic genes are thought to specify relative positions along an axis. Although they may define boundaries of specific structures within a phylum, these structural boundaries are not generally considered to be maintained between phyla. However, data presented by C. Tabin (Boston, USA) suggest that some boundaries defined by Hox genes in vertebrates may indeed be conserved in insects. The anterior boundaries of expression of particular Hox paralog groups in the mesoderm of mouse and chicken correlate with transitions between vertebral types; for example, the genes of paralog group 6 are expressed at the cervical-thoracic border, while group 9 genes are expressed at the thoracic-abdominal border. Expression of these genes therefore correlates with vertebral identity, rather than absolute or relative positions in the embryo. Conservation of these transitions appears to extend to the type of segment specified by the insect homologs of these genes; for example, the Drosopbaa homologs of vertebrate paralog groups 6-8 and 9.-13 are also expressed within the same segment types, Thus the body plan of the common ancestor of insects and vertebrates may have been divided into large-scale morphological units, retained in these animals today. Other body parts of vertebrates and insects may also be homologous at this regulatory level. In the Drosophila alimentary canal, the homeotic genes, which ate expressed primarily along the anteroposterior axis of the visceral mesoderm, control the position of gut constrictions via intercellular signalling molecules such as dpp. Transcription of these signalling molecules is under positive and negative control by the homeotic genes, which also regulate one another, either direcdy or throush growth factor intermediaries (M. Scott, Palo Alto). Intriguingly, Hox genes, as well as Bmpi (a homolog of

Correction: Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation

This corrects the article DOI: 10.1038/386366a0