Fate mapping of the mouse midbrain-hindbrain constriction using a site-specific recombination system.

The mouse midbrain-hindbrain constriction is centrally involved in patterning of the midbrain and anterior hindbrain (cerebellum), as revealed by recent genetic studies using mice and embryological studies in chick (reviewed in [1,2]). This region can act as an organizer region to induce midbrain and cerebellar development. Genes such as Engrailed-1, Pax-2 and Pax-5, which are expressed in the embryonic cells that will form the midbrain and the cerebellum, are required for development of these regions. Fate-mapping experiments at early somite stages in chick have revealed that the cerebellar primordium is located both anterior and posterior to the midbrain-hindbrain constriction, whereas midbrain precursors lie more anteriorly. Fate mapping in mice has been complicated by the inaccessibility of the postimplantation embryo. Here, we report the use of a new in vivo approach involving the Cre-IoxP site-specific recombination system [3] to map the fate of cells in the mouse midbrain-hindbrain constriction. We show that cells originating in the mouse dorsal midbrain-hindbrain constriction during embryonic days 9-12 contribute significantly to the medial cerebellum and colliculi. Our data demonstrate the feasibility of using a recombinase-based lineage-tracing system for fate mapping in the mouse.

Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.

In both vertebrate and invertebrate development, cells are often programmed to adopt fates distinct from their neighbors. Genetic analyses in Drosophila melanogaster have highlighted the importance of cell surface and secreted proteins in these cell fate decisions. Homologues of these proteins have been identified and shown to play similar roles in vertebrate development. Fringe, a novel signalling protein, has been shown to induce wing margin formation in Drosophila. Fringe shares significant sequence homology and predicted secondary structure similarity with bacterial glycosyltransferases. Thus fringe may control wing development by altering glycosylation of cell surface and/or secreted molecules. Recently, two fringe genes were isolated from Xenopus laevis. We report here the cloning and characterization of three murine fringe genes (lunatic fringe, manic fringe and radical fringe). We find in several tissues that fringe expression boundaries coincide with Notch-dependent patterning centres and with Notch-ligand expression boundaries. Ectopic expression of murine manic fringe or radical fringe in Drosophila results in phenotypes that resemble those seen in Notch mutants.

Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development.

The correct patterning of vertebrate skeletal elements is controlled by inductive interactions. Two vertebrate hedgehog proteins, Sonic hedgehog and Indian hedgehog, have been implicated in skeletal development. During somite differentiation and limb development, Sonic hedgehog functions as an inductive signal from the notochord, floor plate and zone of polarizing activity. Later in skeletogenesis, Indian hedgehog functions as a regulator of chondrogenesis during endochondral ossification. The vertebrate Gli zinc finger proteins are putative transcription factors that respond to Hedgehog signaling. In Drosophila, the Gli homolog cubitus interruptus is required for the activation of hedgehog targets and also functions as a repressor of hedgehog expression. We show here that Gli2 mutant mice exhibit severe skeletal abnormalities including cleft palate, tooth defects, absence of vertebral body and intervertebral discs, and shortened limbs and sternum. Interestingly, Gli2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241-246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives. Although Gli2 and Gli3 are not functionally equivalent, double mutant analysis indicates that, in addition to their specific roles, they also serve redundant functions during skeletal development. The role of Gli2 and Gli3 in Hedgehog signaling during skeletal development is discussed.

Drosophila awdK-pn, a homologue of the metastasis suppressor gene nm23, suppresses the Tum-1 haematopoietic oncogene.

The human nm23-H1 gene is a suppressor of solid tumour metastasis in some types of cancer. It is known that nm23 genes encode nucleoside diphosphate kinase polypeptides, but the regulatory pathways involving Nm23 are unclear. One approach to understanding nm23 function is to identify loci which interact with nm23. The Drosophila awd gene, a homologue of nm23, provides a model system for this genetic analysis. We report that the dominant awdK-pn allele suppresses haematopoietic defects associated with the Tum-l oncogene. Premature differentiation and aggregation of Tum-l blood cells is reduced by awdK-pn, resulting in an increased survival of Tum-l hemizygotes. Tum-l lethality is also suppressed by pn mutations, indicating the existence of a haematopoietic regulatory pathway involving the Tum-l, AwdK-pn and Pn proteins.

Mandatory continuing pharmacy education in Alberta, Canada: the response to live programs and correspondence courses.

This report briefly describes mandatory continuing pharmacy education in Alberta and provides survey data to determine the response of pharmacists to the program. The survey results indicate that most pharmacists exceeded the required number of education units and that more than 70 percent of the total acquired were obtained by completing correspondence courses. Females, those under 40 years of age and retail staff preferred correspondence programs. Managers, hospital staff and those over 40 years of age took somewhat fewer education units by correspondence, but attended more live programs than the former group. The popularity of correspondence is presumably due to the fact that most were provided free and because they are a more convenient method of obtaining education units. The freedom allowed to design their own educational program plus the modest costs involved are probably the two main reasons for the acceptability of Albert's continuing education program to pharmacists.