The T/t complex on mouse chromosome 17 which includes the major histocompatibility complex (MHC), also contains a number of mutant gene that affect the differentiation of spermatozoa, and others that function during early embryonic development. Thus, it has been intensively investigated as model system for analyzing both immunobiology and differentiation, and their genetic control. Until recently, however, the molecular biology of the tau-complex was limited to chromosomal walking, marker identification, and random screening. This phase has now been accomplished. New results from this laboratory, obtained with a combination of genetic and molecular techniques have shown that the MHC has become the site major interest in the tau-complex and provided the tools to investigate a gene complex that regulates development in a mammal. Five out of six newly cloned male germ-cell-expressed genes residing in the MHC show expression changes in wild type versus tau-mutant testis. In terms of early embryo development, of the four recessive, early embryo tau-lethal genes interspersed with MHC genes , two have been more precisely located: tw5 is genetically inseparable from H-2K, and one of the earliest acting mammalian lethals, t12, is located either in the TL region or the uncloned """"""""gap"""""""" between the TL and Qalpha regions. The early-embryo expressed transcription factor, Oct-4, has also been mapped to the gap between TL and Qalpha, and preliminary studies indicate it may well be t12. This project proposes three complementary strategies to define the molecular and biological function of these interesting tau-complex genes. (1) Analyze the cloned testis-expressed genes at the transcriptional, translational, and protein level. Ultimately, we will employ transgenic technology to study their dominant function. (2) Identify and map cloned genes, both from our laboratory and others, that are transcribed from within the tau-complex, and expressed in early mouse embryos. We will concentrate on those that are candidates for the tau-lethal mutation. Currently, this includes Oct-4 and six other early embryonic tau/tau complex encoded cDNAs. (3) Recombinational genetic analysis of the tau/tau complex region to support the molecular and functional analysis. Our long- term objective is to understand the molecular mechanisms and genetic control of cellular commitment.
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