In Drosophila, much has been learned about the specification of neuronal cell fates but little is known about the lineage of mesodermal cells with different developmental fates. Initially in development, individual mesodermal precursor cells are singled out to become the founder cells for specific muscles. The selection of muscle founder cells is thought to employ a Notch-mediated process of lateral inhibition, similar to what is observed for the specification of neural precursors. These muscle founder cells then seem to fuse with the surrounding, uncommitted myocytes inducing the formation of muscle fiber syncytia. In contrast, the differentiated progeny of neural precursor cells are usually the result of a fixed pattern of asymmetric cell divisions which are directed, in part, by interactions between numb, a localized intracellular-receptor protein, sanpodo (spdo), a potential tropomodulin homolog, and Notch, a transmembrane receptor protein. Here, we have investigated the role of these neural lineage genes in the cell fate specification of muscle and heart precursors. In particular, we have focused on a progenitor cell that is likely to produce a mixed lineage, generating both a pericardial heart cell and a somatic muscle founder cell. We show that the asymmetric segregation of Numb into one of these daughter cells antagonizes the function of Notch and spdo by preventing the presumptive muscle founder from assuming the same fate as its cardiac sibling. Our results suggest that asymmetric cell divisions, in addition to the previously-documented inductive mechanisms, play a major role in cardiac and somatic muscle patterning and that additionally the cytoskeleton may have a role in the asymmetrical localization of cell fate determinants.

The Drosophila selector gene cut is a hierarchal regulator of external sensory organ identity and is required to pattern the sensory and nonsensory cells of the wing margin. Cut performs the latter function, in part, by maintaining expression of the secreted morphogen encoded by wingless (wg). We find that Cut is required for wing-margin sensory organ specification in addition to and independently of Wg maintenance. In addition, we performed a genetic modifier screen to identify other genes that interact with cut in the regulation of wing-margin patterning. In total, 45 genetic loci (35 gain-of-function and 10 loss-of-function loci) were identified by virtue of their ability to suppress the wing-margin defects resulting from gypsy retrotransposonmediated insulation of the cut wing-margin enhancer. Further genetic characterization identified several subgroups of candidate cut interacting loci. One group consists of putative regulators of gypsy insulator activity. A second group is potentially required for the regulation of Cut expression and/or activity and includes longitudinals lacking, a gene that encodes a family of BTB-domain zinc-finger transcription factors. A third group, which includes a component of the Brahma chromatin remodeling complex encoded by moira, affects the level of Cut expression in two opposing ways by suppressing the gypsy-mediated ct K phenotype and enhancing the non-gypsy ct 53d phenotype. This suggests that the Brahma complex modulates both enhancer-controlled transcription and gypsy-mediated gene insulation of the cut locus. SELECTOR genes are hierarchal regulators of develtranscriptional and cell-signaling networks that indiopmental programs controlling tissue and cell-type rectly link selector gene activity with realizator functions diversification. The highly conserved Hox class of ho-(reviewed in Mann and Carroll 2002; Hombria and meotic selector genes, which control the specification Lovegrove 2003). Thus, to understand how selector of regional identity along the anterior/posterior axis, genes define alternative developmental states, it is necesexemplifies the ability of selector genes to instructively sary to identify the downstream regulatory networks, as direct the selection between alternative developmental well as the realizator genes, which ultimately carry out states. For instance, gain-of-function mutations in the the selected developmental program. Hox gene Antennapedia (Antp), resulting in the inappro-The Drosophila melanogaster gene cut is a neural selecpriate expression of Antp protein in imaginal antennal tor gene, which establishes the developmental program tissue, lead to complete antenna-to-leg transformations directing external sensory (ES) organ identity. The pe- (Schneuwly et al. 1987). It has been proposed that ripheral nervous system is composed of diverse types of selector genes function by coordinating the serial activsensory organs, including ES organs (cuticular mechaity of "realizator" genes (i.e., those genes that intimately nosensory and chemose...

The Numb protein is involved in cell fate determination during Drosophila neural development. Numb has a protein domain homologous to the phosphotyrosinebinding domain (PTB) in the adaptor protein Shc. In Shc, this domain interacts with specific phosphotyrosine containing motifs on receptor tyrosine kinases and other signaling molecules. Residues N-terminal to the phosphotyrosine are also crucial for phosphopeptide binding to the Shc PTB domain. Several amino acid residues in Shc have been implicated by site-directed mutagenesis to be critical for Shc binding to receptor tyrosine kinases. We have generated homologous mutations in Numb to test whether, in vivo, these changes affect Numb function during Drosophila sensory organ development. Two independent amino acid changes that interfere with Shc binding to phosphotyrosine residues do not affect Numb activity in vivo. In contrast, a mutation shown to abrogate the ability of the Shc PTB domain to bind residues upstream of the phosphotyrosine virtually eliminates Numb function. Similar results were observed in vitro by examining the binding of the Numb PTB domain to proteins from Schneider S2 cells. Our data confirm the importance of the PTB domain for Numb function but strongly suggest that the Numb PTB domain is not involved in phosphotyrosine-dependent interactions.

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