FlyBase () is a database of genetic and genomic data on the model organism Drosophila melanogaster and the entire insect family Drosophilidae. The FlyBase Consortium curates, annotates, integrates and maintains a wide variety of data within this domain. Access to the data is provided through graphical and textual user interfaces tailored to particular types of data. FlyBase data types include maps at the cytological, genetic and sequence levels, genes and alleles including their products, functions, expression patterns, mutant phenotypes and genetic interactions as well as aberrant chromosomes, annotated genomes, genetic stock collections, transposons, transgene constructs and insertions, anatomy and images, bibliographic data, and community contact information.

The activation signal from tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), is relayed via a highly conserved intracellular pathway involving Ras, Raf, and MAPK. In Drosophila, the EGFR and components of the intracellular pathway are broadly expressed, yet receptor activation evokes tissue-specific cell responses. Extracellular events that lead to receptor activation are one mechanism by which signaling is modulated. Here we show molecular and genetic evidence that Drosophila vein (vn) encodes a candidate EGFR ligand and that vn expression is spatially restricted. Consequently, vn may promote tissue-specific receptor activation. Unlike two other ligands, Gurken (Grk) and Spitz (Spi), which are transforming growth factor oMike proteins, Vn has both an immunoglobulin-like and an EGF-like domain. This combination of domains mirrors those in the vertebrate neuregulins that bind EGFR relatives. [Key Words: vein; Drosophila; EGF receptor; EGF; neuregulin]Received April 24, 1996; revised version accepted August 7, 1996.The Drosophila epidermal growth factor receptor (DER) is a receptor tyrosine kinase of the epidermal growth factor receptor (EGFR) subfamily that currently also includes four vertebrate proteins {EGFR/erbB1, neu/erbB2, erbB3, and erbB4) and Caenorhabditis elegans These receptors have important roles in development: EGFR mutant mice have epithelial defects that cause a number of phenotypes and early death (Miettinen et al. 1995;Sibilia and Wagner 1995;Threadgill et al. 1995); neu and erbB4 mutant embryos die in utero with heart and neural defects (Gassmann et al. 1995;Lee et al. 1995); let-23 is involved in determining vulval cell fate (Aroian et al. 1990; Hill and Sternberg 19921; and DER has multiple roles in Drosophila development involving cell survival, proliferation, and differentiation in embryos, imaginal discs, and the ovary (Shilo and

BackgroundAnatomy ontologies are query-able classifications of anatomical structures. They provide a widely-used means for standardising the annotation of phenotypes and expression in both human-readable and programmatically accessible forms. They are also frequently used to group annotations in biologically meaningful ways. Accurate annotation requires clear textual definitions for terms, ideally accompanied by images. Accurate grouping and fruitful programmatic usage requires high-quality formal definitions that can be used to automate classification and check for errors. The Drosophila anatomy ontology (DAO) consists of over 8000 classes with broad coverage of Drosophila anatomy. It has been used extensively for annotation by a range of resources, but until recently it was poorly formalised and had few textual definitions.ResultsWe have transformed the DAO into an ontology rich in formal and textual definitions in which the majority of classifications are automated and extensive error checking ensures quality. Here we present an overview of the content of the DAO, the patterns used in its formalisation, and the various uses it has been put to.ConclusionsAs a result of the work described here, the DAO provides a high-quality, queryable reference for the wild-type anatomy of Drosophila melanogaster and a set of terms to annotate data related to that anatomy. Extensive, well referenced textual definitions make it both a reliable and useful reference and ensure accurate use in annotation. Wide use of formal axioms allows a large proportion of classification to be automated and the use of consistency checking to eliminate errors. This increased formalisation has resulted in significant improvements to the completeness and accuracy of classification. The broad use of both formal and informal definitions make further development of the ontology sustainable and scalable. The patterns of formalisation used in the DAO are likely to be useful to developers of other anatomy ontologies.

vein1 (vn1) mutants lack portions of longitudinal wing vein 4 and the anterior crossvein. Stronger alleles, originally called defective dorsal discs, show vn is also required for the growth of the wing and haltere discs, as mutants for these alleles have tiny dorsal discs. vn functions nonautonomously and encodes a secreted EGF-like protein. Here we characterize the role of vn in the imaginal wing disc by describing the expression pattern and correlating this pattern with vn mutant phenotypes and the requirement for vn. vn is expressed in wing discs in a complex and dynamic pattern. In larval wing discs vn is first expressed in the presumptive notum and later in the wing-pouch and hinge regions. There is a striking localization of vn transcripts to intervein regions which begins with a stripe of expression straddling the AP boundary in late larval discs and develops in all intervein regions after puparium formation. We isolated new vn mutations including nulls and hypomorphs. Hypomorphic vn alleles revealed region-specific requirements for vn within the wing disc. We mapped lesions caused by 10 vn mutations and defined a minimum size of 48 kb for the gene. The phenotype and expression analyses show vn has an early role in global proliferation of the wing disc and specific roles in the development of the notum, hinge, longitudinal vein 4, and all intervein regions. The role of vn in the EGF receptor signaling pathway is discussed.

In Drosophila the function of the epidermal growth factor (EGF) receptor is modulated zygotically by three EGF-like proteins: Spitz (Spi), which is a potent activator; Vein (Vn), which is a moderate activator; and Argos (Aos), which is an inhibitor. Chimeric molecules were constructed in which the EGF domain of Vn was swapped with the EGF domain from each factor. The modified Vn proteins behaved both in vitro and in vivo with properties characteristic of the factor from which the EGF domain was derived. These results demonstrate that the EGF domain is the key determinant that gives DER inhibitors and activators their distinct properties. Received January 13, 1998; revised version accepted February 10, 1998. The Drosophila epidermal growth factor (EGF) receptor (DER) is a member of the ErbB family of receptor tyrosine kinases (RTKs) and, like its vertebrate counterparts, controls cell differentiation, survival, and proliferation in many tissues throughout development (Perrimon and Perkins 1997;Schweitzer and Shilo 1997). DER function is modulated by four candidate ligands each of which possesses a predicted EGF-like domain. Gurken (Grk) and Spitz (Spi) are TGF␣-like proteins (Rutledge et al. 1992;Neuman-Silberberg and Schü pbach 1993). grk is a maternally active gene involved in establishing egg polarity (Neuman-Silberberg and Schü pbach 1993; Gonzá-lez-Reyes et al. 1995), whereas spi is zygotically active and functions in the embryo, adult eye, and wing (Rutledge et al. 1992;Freeman 1994b). Vn resembles the vertebrate neuregulins in that both possess an Ig-C2 domain in addition to the EGF-like domain . Vein (Vn) functions zygotically in the embryo and the adult wing Simcox et al. 1996;Simcox 1997;Yarnitzky et al. 1997). Here we show that Vn is a moderate activator of DER signaling in comparison with Spi, which is a potent DER activator. Argos (Aos) has been recognized recently as an inhibitor of the DER pathway and was the first extracellular factor shown to inhibit an RTK in vivo (Schweitzer et al. 1995a). Aos functions in the embryo, adult eye, and wing (Freeman et al. 1992;Sawamoto et al. 1994;Golembo et al. 1996).Considerable effort has been made to understand the structure-function relationships of vertebrate EGF-like mitogens to aid in the development of ErbB receptor superagonists or antagonists; however, to date these studies have not led to the design of effective factors (Groenen et al. 1994). The fly system offers a unique opportunity to define the molecular basis for the distinct properties of three natural ligands with different effects on a receptor and could facilitate the development of vertebrate factors with similar relative properties.Spi, Vn, and Aos are structurally unrelated except within the EGF domain (Fig. 1A). The EGF domain contains a series of six cysteines, which form three disulfide bonds to generate a looped structure, and a number of other highly conserved residues that are known to be required for binding and activating members of the vertebrate ErbB receptor family (Groenen ...