Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously. The molecular lesions responsible for 14 mutations were identified, including mutations in nine genes that had not been characterized previously. Some mutations affect vertebrate-specific components of conserved signaling pathways; for example, at least five mutations affect previously uncharacterized regulators of the Sonic hedgehog (Shh) pathway. Approximately half of all of the mutations affect the initial establishment of the body plan, and several of these produce phenotypes that have not been described previously. A large fraction of the genes identified affect cell migration, cellular organization, and cell structure. The findings indicate that phenotype-based genetic screens provide a direct and unbiased method to identify essential regulators of mammalian development.ethylnitrosourea ͉ hedgehog ͉ intraflagellar transport ͉ mesoderm ͉ neural tube closure M ammalian embryogenesis differs fundamentally from the development of other animal models. Localized maternal components are not essential for axis specification in mammals (1), whereas the establishment of the body axes in Drosophila, Caenorhabditis elegans, and zebrafish relies on localization of maternal determinants (2-4). Mammalian development has a unique requirement for complex interactions between embryonic and uterine tissues, and the first cell fate decision in the mouse embryo is the choice between embryonic and extraembryonic lineages (5). After implantation, germ layer organization and tissue specification in the mouse embryo depend on coupled morphogenetic movements and intercellular signals, processes not paralleled in invertebrate embryos. A standard approach to study the genetic control of mouse embryogenesis has been to inactivate evolutionarily conserved genes by targeted mutagenesis; this approach may overlook components that are of particular importance in mammals. In contrast, phenotypebased screens in the mouse have the potential to identify the molecules that control mammalian-specific events.Phenotype-based screens depend on the ability to induce a large number of random mutations in germ cells and on rapid identification of mutants of interest. It has been known for 25 years that ethylnitrosourea (ENU) is an extremely potent mutagen in the mouse (6, 7); and a screen of the progeny of only 700 F 1 progeny of ENU-treated animals should yield an average of one allele of each gene in the genome. We previously described a pilot phenotype-based screen to identify recessive mutations that produce easily visible disruptions in the morphology of the midgestation mouse embryo (8). Similar phenotype-based approaches in other laboratories that focused on later stages of embryonic and fet...
Math1 is a basic helix-loop-helix transcription factor
Metazoans use diverse and rapidly evolving mechanisms to determine sex. In Drosophila melanogaster an X-chromosome-counting mechanism determines the sex of an individual by regulating the master switch gene, Sex-lethal (Sxl). The X-chromosome dose is communicated to Sxl by a set of X-linked signal elements (XSEs), which activate transcription of Sxl through its 'establishment' promoter, SxlPe. Here we describe a new XSE called sisterlessC (sisC) whose mode of action differs from that of previously characterized XSEs, all of which encode transcription factors that activate SxlPe directly. In contrast, sisC encodes a secreted ligand for the Drosophila Janus kinase (JAK) and 'signal transducer and activator of transcription' (STAT) signal transduction pathway and is allelic to outstretched (os, also called unpaired). We conclude that sisC works indirectly on Sxl through this signalling pathway because mutations in sisC or in the genes encoding Drosophila JAK or STAT reduce expression of SxlPe similarly. The involvement of os in sex determination confirms that secreted ligands can function in cell-autonomous processes. Unlike sex signals for other organisms, sisC has acquired its sex-specific function while maintaining non-sex-specific roles in development, a characteristic that it shares with all other Drosophila XSEs.
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