The long-term objective of these studies is to determine how the expression of germ cell specific proteins is regulated post-transcriptionally during spermatogenesis. As a result of chromatin changes during spermiogenesis, post-transcriptional control plays an especially prominent role in regulating gene expression in the developing male gamete. Our past studies have identified a DNA/RNA-binding protein, Testis Brain RNA-binding protein (TB-RBP), that binds to conserved DNA sequences at chromosomal translocation breaks and to RNA sequences of mRNAs that are translationally regulated and transported.
In Specific Aim 1 we propose to determine how a TB-RBP interacting protein Trax modulates the nucleic acid binding activity of TB-RBP using transgenesis.
In Specific Aim 2, TB-RBP and mutated forms of TB-RBP will be over expressed to determine how a disruption in the ratio of TB-RBP and Trax affects spermatogenesis.
In Specific Aim 3, fertility and somatic cell function will be investigated using gene-targeted mice lacking TB-RBP.
In Specific Aim 4, the process whereby TB-RBP facilitates mRNA transport through intercellular bridges will be examined focusing on a kinesin and specific mRNAs encoded on sex chromosomes. These studies will provide important and novel data on critical mechanisms that regulate the expression of many testis-specific gene products essential for the production of functional spermatozoa. Moreover, our findings promise to extend far beyond spermatogenesis and have general applicability to translational regulation and mRNA transport in eukaryotic cells, since TB-RBP plays an important role in the transport and localization of a large number of mammalian brain mRNAs
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