The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition.

Snail family genes encode DNA binding zinc finger proteins that act as transcriptional repressors. Mouse embryos deficient for the Snail (Sna) gene exhibit defects in the formation of the mesoderm germ layer. In Sna(-/-) mutant embryos, a mesoderm layer forms and mesodermal marker genes are induced but the mutant mesoderm is morphologically abnormal. Lacunae form within the mesoderm layer of the mutant embryos, and cells lining these lacunae retain epithelial characteristics. These cells resemble a columnar epithelium and have apical-basal polarity, with microvilli along the apical surface and intercellular electron-dense adhesive junctions that resemble adherens junctions. E-cadherin expression is retained in the mesoderm of the Sna(-/-) embryos. These defects are strikingly similar to the gastrulation defects observed in snail-deficient Drosophila embryos, suggesting that the mechanism of repression of E-cadherin transcription by Snail family proteins may have been present in the metazoan ancestor of the arthropod and mammalian lineages.

Location of mouse and human genes corresponding to conserved canine olfactory receptor gene subfamilies.

Olfactory receptors are G protein-coupled, seven-transmembrane-domain proteins that are responsible for binding odorants in the nasal epithelium. They are encoded by a large gene family, members of which are organized in several clusters scattered throughout the genomes of mammalian species. Here we describe the mapping of mouse sequences corresponding to four conserved olfactory receptor genes, each representing separate, recently identified canine gene subfamilies. Three of the four canine genes detected related gene clusters in regions of mouse Chromosomes (Chrs) 2, 9, and 10, near previously mapped mouse olfactory genes, while one detected a formerly unidentified gene cluster located on mouse Chr 6. In addition, we have localized two human gene clusters with homology to the canine gene, CfOLF4, within the established physical map of Chr 19p. Combined with recently published studies, these data link the four conserved olfactory gene subfamilies to homologous regions of the human, dog, and mouse genomes.

Induced mouse chromosomal rearrangements as tools for identifying critical developmental genes and pathways.

Due to the rapid advances that have been made in molecular and genetic technology during the past decade, the genes associated with a large number of human hereditary diseases have been isolated and analyzed in detail. These cloned genes provide new tools for research geared toward a better understanding of normal human development, and also of the many ways that basic, essential morphologic pathways can be disturbed. Chromosomal rearrangements, especially deletions and translocations, have been especially beneficial in the mapping and isolation of human disease genes because of their visibility on both the cytogenetic and molecular levels. However, these useful types of mutations occur with low frequency in the human population. Chromosomal rearrangements can be induced relatively easily in mice, and several large, independent collections of translocation and deletion mutants have been generated in the course of risk-assessment and mutagenesis studies over the past several decades. Combined with new molecular technologies, these collections of mutant animals provide a means of gaining ready access to genes associated with developmental defects including craniofacial abnormalities, hydrocephaly, skeletal deformities, and complex neurologic disorders. As an illustration of this approach, we briefly review our progress in the study of three mutations associated with defects in palate development, juvenile growth, fitness and sterility, and neurologic development in mice, respectively.

Zooming in on the human-mouse comparative map: genome conservation re-examined on a high-resolution scale.

Over the past decade, conservation of genetic linkage groups has been shown in mammals and used to great advantage, fueling significant exchanges of gene mapping and functional information especially between the genomes of humans and mice. As human physical maps increase in resolution from chromosome bands to nucleotide sequence, comparative alignments of mouse and human regions have revealed striking similarities and surprising differences between the genomes of these two best-mapped mammalian species. Whereas, at present, very few mouse and human regions have been compared on the physical level, existing studies provide intriguing insights to genome evolution, including the observation of recent duplications and deletions of genes that may play significant roles in defining some of the biological differences between the two species. Although high-resolution conserved marker-based maps are currently available only for human and mouse, a variety of new methods and resources are speeding the development of comparative maps of additional organisms. These advances mark the first step toward establishment of the human genome as a reference map for vertebrate species, providing evolutionary and functional annotation to human sequence and vast new resources for genetic analysis of a variety of commercially, medically, and ecologically important animal models.

Generation and characterization of heritable reciprocal translocations in mice.

Reciprocal translocations have provided crucial tools for the localization of genes associated with a variety of human cancers and hereditary diseases. Although heritable translocations are relatively rare in humans, they can be easily induced in mice through exposure of male germ cells at specific spermatogenic stages to different types of radiation and chemicals. Mutagenesis schemes that produce translocations at high frequencies in the progeny of treated males are summarized, and the use of these valuable mutations for analyzing developmental consequences of partial aneuploidy, for identification of mutant genes, and for other purposes is reviewed. Preliminary studies of a large collection of translocation mutants, including several stocks that display dominantly or recessively inherited phenotypes caused by the disruption of critical genes are described. These combined studies demonstrate that several mutagenesis protocols can be used to generate easily mapped, novel mouse mutations with high efficiency and highlight the unique value of reciprocal translocations as tools for gaining access to the biological functions of mammalian genes.

Detailed comparative map of human chromosome 19q and related regions of the mouse genome.

One of the larger contiguous blocks of mouse-human genomic homology includes the proximal portion of mouse chromosome 7 and the long arm of human chromosome 19. Previous studies have demonstrated the close relationship between the two regions, but have also indicated significant rearrangements in the relative orders of homologous mouse and human genes. Here we present the genetic locations of the homologs of 42 human chromosome 19q markers in the mouse, with an emphasis on genes also included in the human chromosome 19 physical map. Our results demonstrate that despite an overall inversion of sequences relative to the centromere, apparent "transpositions" of three gene-rich segments, and a local inversion of markers mapping near the 19q telomere, gene content, order, and spacing are remarkably well conserved throughout the lengths of these related mouse and human regions. Although most human 19q markers have remained genetically linked in mouse, one small human segment forms a separate region of homology between human chromosome 19q and mouse chromosome 17. Three of the four rearrangements of mouse versus human 19q sequences involve segments that are located directly adjacent to each other in 19q13.3-q13.4, suggesting either the coincident occurrence of these events or their common association with unstable DNA sequences. These data permit an unusually in-depth examination of this large region of mouse-human genomic homology and provide an important new tool to aid in the mapping of genes and associated phenotypes in both species.