GENES REGULATING PATTERN FORMATION DURING EMBRYONIC DEVELOPMENT

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Many key processes in morphogenesis, including responses to trophic stimuli, cell-cell interactions, migration, differential cell multiplication, and programmed cell death, are recapitulated in a pathologic manner during oncogenesis and metastasis, suggesting an aberrant regulation or 're-activation' of such processes. The chick embryo is attractive for studying the regulation of pattern formation and morphogenesis because of accessability of the embryo to manipulation, amenability to biochemical and molecular analyses, and a high degree of conservation with mammalian development. Hence, genes isolated in the chick can also be analyzed using molecular genetic approaches in the mouse embryo. The aim of this project is to isolate developmental control genes that regulate pattern formation; in particular, the patterning of the primary embryonic axis and the appendicular axis. Many of the same regulatory and signalling cascades appear to operate during both of these processes. Several new transcription factors have been isolated (homeobox and brachyury-related genes) that are specifically and selectively expressed during gastrulation and limb development. The homeobox gene Hoxd-12 plays a role in determining the anteroposterior pattern of bones in the limb. Gnot1 and Gnot2 homeobox genes are expressed in tissues with 'organizer' activity during gastrulation and may play a role in the formation and/or activity of a 'trunk/tail' organizer. Gnot1 is also expressed in the limb bud and may regulate proximodistal limb pattern. Several new members of the brachyury gene family, a new type of transcription factor known to be critical in the formation of the embryonic axis in mouse, have been isolated in the chick (Gbra1-3). These brachyury-related genes are expressed in partly overlapping domains of 'organizer' tissues during gastrulation. Interestingly, one of these genes is also expressed in the developing limb bud. Studies are underway to further elucidate the function of these new homeobox and brachyury members, using molecular-genetic and biochemical approaches in chick and mouse embryos.