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Emc, a Negative HLH Regulator with Multiple Functions in Drosophila Development

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Emc, a Negative HLH Regulator with Multiple Functions in Drosophila Development Oncogene (2001) 20, 8299 ± 8307 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Emc, a negative HLH regulator with multiple functions in Drosophila development Sonsoles Campuzano*,1 1Centro de BiologõÂa Molecular Severo Ochoa, Cantoblanco, 28049 Madrid, Spain Expression and functional analyses of Emc have which by their own do not alter the pattern of SOs, a demonstrated that it is a prototype for a protein required recessive mutation in a gene encoding a repressor of for multiple processes in development. Initially char- AS-C would become dominant and promote the acterized as a negative regulator of sensory organ generation of extra SOs. That is, only one copy of development, it was later found to regulate many other that gene would not produce enough protein to repress developmental processes and cell proliferation. Its ability several copies of AS-C and allow a normal pattern of to block the function of bHLH proteins by forming SOs. Mutations that ful®lled this criterion were found heterodimers, which are ineective in DNA binding, in two loci: hairy (h) and the novel emc (Botas et al., accounts for the role of Emc in preventing the acquisition 1982). It was further observed that loss of emc of several cell fates which are under the control of bHLH function, in a wild type background for the AS-C, proteins. However, while maintaining this repressive caused development of extra SOs, whereas AS-C molecular mechanism, emc also appears to act as a de®ciencies suppressed this phenotype (Moscoso del positive regulator of dierentiation. Oncogene (2001) Prado and GarcõÂ a-Bellido, 1984a,b). Taken together, 20, 8299 ± 8307 these results suggested that the generation of extra SOs in emc mutants depended on the activity of the AS-C Keywords: Drosophila; extramacrochaetae; HLH; tran- and not on the modi®cation of a parallel develop- scription factor; development mental pathway. The molecular analysis of AS-C and emc con®rmed this hypothesis and provided a molecular basis for the negative regulation of AS-C Identi®cation of extramacrochaetae by emc. According to the usual nomenclature system of Drosophila genes, the extramacrochaetae (emc) gene Emc titrates away proneural proteins was named after the ®rst discovered phenotype associated to its loss-of-function mutations, i.e., the The achaete (ac)andscute (sc) genes encode proteins development of extra sensory organs (SOs) on the which contain the basic ± helix ± loop ± helix domain adult ¯y. The larval and adult epidermis of Drosophila (bHLH) characteristic of a family of transcriptional contains thousands of SOs that are distributed regulators (Murre et al., 1989a; Villares and Cabrera, according to a stereotyped pattern. Each SO is formed 1987; see Massari and Murre, 2000, for a recent by the progeny of a single cell, the sensory mother cell review). Biochemical analysis of mammalian bHLH (SMC), which, during the third larval instar or early proteins involved in myogenesis, the MyoD family, and pupal stages, is singled out from the population of of immunoglobulin enhancer binding bHLH proteins imaginal discs cells or abdominal histoblasts (Bate, E12 and E47, showed that the HLH domain allows 1978; Bodmer et al., 1989; GarcõÂ a-Bellido and these proteins to form homodimers or heterodimers Merriam, 1971; Hartenstein and Posakony, 1989). with other members of the family, while the basic Genetic analysis of loss and gain-of-function mutations region is required for binding to speci®c DNA in the achaete-scute complex (AS-C) indicated that it sequences (Murre et al., 1989b). ac and sc are was involved in the commitment of epidermal cells to expressed at the right place and time to promote dierentiate as SOs and that the AS-C might be under SMC determination, as anticipated by the genetic some type of negative regulation (GarcõÂ a-Bellido and analyses. Both genes are coexpressed in the wing SantamarõÂ a 1978; GarcõÂ a-Bellido, 1979). Back in the imaginal discs, the anlagen of most of the thorax and early eighties, a genetic screen was performed to the wings, in clusters of cells located at precisely identify genes that might negatively regulate the AS- determined positions (Cubas et al., 1991; Romani et C (Botas et al., 1982). The rationale of the screening al., 1989; Skeath and Carroll, 1991) (Figure 1a). SMCs was that in the presence of extra doses of the AS-C, are born within these clusters of ac ± sc expressing cells (Cubas et al., 1991; Skeath and Carroll, 1991) (Figure 1a). Moreover, removal of speci®c proneural clusters in *Correspondence: S Campuzano; E-mail: [email protected] ac or sc mutants removes the corresponding SMCs and Multiples requirements for Emc in development S Campuzano 8300 Figure 1 Relationship between the pattern of expression of sc (a) and emc (b, c) in the imaginal wing disc and the pattern of SMCs. (a) Imaginal wing disc from an enhancer trap line that expresses lacZ (green) in the SMCs. The distribution of sc mRNA, revealed by in situ hybridization, is shown in purple. Note that SMCs are born within the clusters of sc expressing cells. (b) Pattern of expression of emc. It is fairly complementary to that of sc. Note minima of emc expression at the regions where the SMCs for the DC and SC bristles develop. (c) Expression of emc (purple) and distribution of SMCs (green) in a Hairy wing imaginal wing disc. (Only the prospective wing region is shown). Although sc is ubiquitously expressed in Hairy wing discs (Balcells et al., 1988), expression of emc is not modi®ed (compare with b). Note the development of ectopic SMCs at the posterior wing margin (PWM) that arise within a region of minimal emc expression. Positions of some SMCs is indicated, namely those that will give rise to the anterior notopleural bristle (ANP); anterior postalar bristle (APA); anterior wing margin bristles (AWM); dorsocentral bristles (DC); giant sensilum of the radius (GSR); sensilla of the dorsal radius (Rd); scutellar bristles (SC) and sensilla of the tegula (Td). PWB, posterior wing blade; v3, vein 3 SOs (Cubas et al., 1991; Romani et al., 1989; Skeath development of extra SOs in ectopic positions (Balcells and Carroll, 1991) and a generalized distribution of et al., 1988; Skeath and Carroll, 1991). Since AS-C Ac ± Sc products (in Hairy wing mutants) promotes proteins confer on cells the ability to become neural Oncogene Multiples requirements for Emc in development S Campuzano 8301 precursors, the AS-C genes have been called proneural genes and the clusters of cells expressing them are referred to as the proneural clusters (Ghysen and Dambly-ChaudieÁ re, 1989; Romani et al., 1989). Another bHLH protein Daughterless (Da), previously identi®ed by its role in sex determination (Cline, 1989) acts synergistically with Ac/Sc to build the SO pattern (Caudy et al., 1988a,b; Dambly-ChaudieÁ re et al., 1988). HLH proteins have been classi®ed according to tissue distribution, dimerization capabilities and DNA-bind- ing site speci®city (Massari and Murre, 2000). Due to their restricted pattern of expression, Ac and Sc belong to HLH class II. On the contrary, Da belongs to class I HLH proteins, which show a generalized distribution (Massari and Murre, 2000). Usually, class II HLH proteins activate transcription in the form of hetero- dimers with class I HLH proteins (Massari and Murre, 2000). Thus, the molecular structure of As ± Sc and Da as well as their genetic interactions (Caudy et al., 1988a,b; Dambly-ChaudieÁ re et al., 1988; Villares and Cabrera, 1987) indicated that they are transcriptional regulators that, in combination, control the activity of genes involved in SMC commitment. In agreement with this hypothesis, AS-C proteins and Da can form heterodimers that bind to speci®c DNA sites in vitro (Cabrera et al., 1987; Murre et al., 1989b). emc also encodes a transcription factor of the HLH family, but the Emc protein lacks the basic region that is involved in the interaction with DNA (Ellis et al., 1990; Garrell and Modolell, 1990) and thus, it belongs to class V of HLH proteins (Massari and Murre, 2000). Heterodimers formed by a bHLH protein and an HLH protein devoid of the basic region are unable to bind to DNA (Davis et al., 1990; Voronova and Baltimore, 1990). Since it was already demonstrated that proneur- al proteins speci®cally bind to DNA in the form of heterodimers (Murre et al., 1989b), a plausible hypothesis for the regulatory interactions between Emc and AS-C was put forward (Figure 2a). Emc would antagonize proneural ac ± sc function by seques- tering proneural bHLH proteins in complexes incap- Figure 2 Possible mechanisms for Emc action. (a) Depicts the situation in an SMC. Sc and Da form heterodimers that are able able of eective interaction with DNA, rather than by to bind to DNA. The black rectangles indicate that the binding a direct repression of AS-C transcription (Ellis et al., domain of this heterodimer ®ts into the binding site present in the 1990; Garrell and Modolell, 1990, reviewed in Garrell promoter of the target gene. Sc/Emc and Da/Emc heterodimers and Campuzano, 1991). This mechanism would are unable to bind to DNA (indicated by the white rectangle). Commitment to the SMC fate takes place in cells like that shown account for the dose dependent interactions between in (a) in which the concentration of active heterodimers exceeds emc, as, sc and da, which suggested that a ®nely tuned that of ineective heterodimers, thus allowing activation of target balance of proneural proteins and of Emc was required gene promoter. In this case Emc plays a repressive role. A similar for proper SMC determination.
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