Review 3022tissue movements as in the adult, although on a much smaller scale, but only at late foetal stages is healing accompanied by an inflammatory response (Hopkinson-Woolley et al., 1994; Cowin et al., 1998). Prior to these stages, inflammation is absent and the embryo is capable of essentially perfect, near regenerative repair, with no resulting scar. Wound healing, even in the embryo (Fig. 2), is a complex process involving the coordination of several cell behaviours from several different cell types, and for each stage of wound repair there are fundamental cell biology issues that still need resolving (see Box 1). Developmental models of wound healingA number of naturally occurring morphogenetic events involve tissue movements similar to those required for wound healing. Two of the clearest of these, both of which involve closure of epithelial holes, are dorsal closure in the Drosophila embryo and C. elegans ventral enclosure. Dorsal closure in DrosophilaNear the end of the complex and intricately orchestrated cell and tissue movements of Drosophila gastrulation, including the extension of the germband over the dorsal surface and its subsequent retraction, a large hole is left behind on the dorsal surface of the embryo. An extra-embryonic membrane consisting of large flat cells -the amnioserosa -covers this dorsal hole (Fig. 3A-D). The process of bringing together the two epithelial edges over the amnioserosa to close the hole and form a seamless dorsal midline is known as dorsal closure. The dorsal hole is elliptical or eye shaped, and closure proceeds from the anterior and posterior ends (or canthi) of the opening towards the middle. The integrated efforts of three groups of cells are required for proper closure: the dorsalmost row of ectodermal cells defining the perimeter of the epithelial sheet, termed the leading edge (LE) cells; the more ventral epithelial (VE) cells; and the exposed amnioserosa (AS). Dorsal closure has been described as taking place in four phases (for detailed descriptions, see Harden, 2002;Jacinto et al., 2002b). The first phase, initiation (Fig. 3A), begins just prior to the completion of germband retraction, with the two opposing epithelial sheets moving slowly towards one another as a consequence of amnioserosal cell contraction. The trigger(s) required to start the dorsal closure process are not known, but probably include a combination of chemical and mechanical cues, including dorsoventral patterning information and mechanical stresses generated by germband retraction.During the second phase, epithelial sweeping ( Fig. 3B), leading edge cells accumulate actin and myosin just beneath the cell membrane at their dorsalmost (apical) edge. This Factin accumulation forms a contractile cable, which pulls the leading edges of the epithelial sheets taut (Jacinto et al., 2002a) Development 131 (13) Fig. 1. The cellular players in the healing of a skin wound. The wound is first 'plugged' with a fibrin clot, which is infiltrated by inflammatory cells, fibroblasts and a dense plexus...

The Myc/Max/Mad transcription factor network is critically involved in cell behavior; however, there is relatively little information on its genomic binding sites. We have employed the DamID method to carry out global genomic mapping of the Drosophila Myc, Max, and Mad/Mnt proteins. Each protein was tethered to Escherichia coli DNA adenine-methyltransferase (Dam) permitting methylation proximal to in vivo binding sites in Kc cells. Microarray analyses of methylated DNA fragments reveals binding to multiple loci on all major Drosophila chromosomes. This approach also reveals dynamic interactions among network members as we find that increased levels of dMax influence the extent of dMyc, but not dMnt, binding. Computer analysis using the REDUCE algorithm demonstrates that binding regions correlate with the presence of E-boxes, CG repeats, and other sequence motifs. The surprisingly large number of directly bound loci (∼ 15% of coding regions) suggests that the network interacts widely with the genome. Furthermore, we employ microarray expression analysis to demonstrate that hundreds of DamID-binding loci correspond to genes whose expression is directly regulated by dMyc in larvae. These results suggest that a fundamental aspect of Max network function involves widespread binding and regulation of gene expression.[Keywords: myc; mad; Drosophila; target genes; transcription] Supplemental material is available at http://parma.fhcrc.org/AOryan.

hairy is a Drosophila pair-rule segmentation gene that functions genetically as a repressor. To isolate protein components of Hairy-mediated repression, we used a yeast interaction screen and identified a Hairyinteracting protein, the Drosophila homolog of the human C-terminal-binding protein (CtBP). Human CtBP is a cellular phosphoprotein that interacts with the C-terminus of the adenovirus E1a oncoprotein and functions as a tumor suppressor. dCtBP also interacts with E1a in a directed yeast two-hybrid assay. We show that dCtBP interacts specifically and directly with a small, previously uncharacterized C-terminal region of Hairy. dCtBP activity appears to be specific to Hairy of the Hairy/Enhancer of split [E(spl)]/Dpn basic helix-loop-helix protein class. We identified a Pelement insertion within the dCtBP transcription unit that fails to complement alleles of a known locus, l(3)87De. We demonstrate that dCtBP is essential for proper embryonic segmentation by analyzing embryos lacking maternal dCtBP activity. While Hairy is probably not the only segmentation gene interacting with dCtBP, we show dose-sensitive genetic interactions between dCtBP and hairy mutations.