Male germ cells contain a large number of isoprotein variants for common enzymes and structural proteins. The long term objective of this study is to understand the biological importance of isozyme/isoprotein substitutions in the mammalian testis and the mechanisms that regulate spermatogenesis. Specifically, efforts will focus on the mechanisms regulating the coordinate up-regulation and down-regulation of the cytochromes c in the mammalian testis.
In specific aim 1, mice lacking the testis/male germ cell-specific cytochrome cT isoprotein will be produced by gene targeting to determine whether cytochrome cT is essential for spermatogenesis and examine the mechanism of cross-talk between the two testicular cytochromes c genes in the cytochrome cT deficient mice.
In specific aim 2, in vitro analyses of the putative cis-acting DNA elements and the transacting protein factors that bind to these putative elements to regulate the somatic cell-type, cytochrome cs, and the male germ cell-type, cytochrome cT, expression will be conducted.
In specific aim 3, the mechanism(s) by which the 5' untranslated regions of the cytochrome cT mRNAs modulate translation of the isoprotein will be studied. The experiments described in this proposal will attempt to determine the mechanisms whereby a ubiquitous mitochondrial protein is replaced at a specific stage of male germ cell differentiation by a testis specific protein variant and whether this coordinate regulation of gene expression is a prerequisite for normal spermatogenesis and maintenance of fertility. In addition, these studies may elucidate a mechanism of general interest for the coordinate down-regulation and up-regulation of specific genes in highly differentiated mammalian cells.
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