The production of gametes in mammals is an elaborate process that begins during embryogenesis and continues during the reproductive life of the organism. Gametogenesis involves the production of highly specialized cells with unique organelles designed to accomplish the union of sperm and egg at fertilization. The timely production of developmentally important products involves the regulated translation of mRNAs that have accumulated earlier during gametogenesis. Deviation from the wild-type timing of translation can cause cessation of gametogenesis and lead to sterility in mice. Loss of posttranscriptional control may be responsible for a significant percentage of idiopathic male infertility in humans. Our understanding of the genetic control and molecular mechanisms of posttranscriptional control during gametogenesis is woefully incomplete. The long-term goal of this proposal is to elucidate the mechanisms of translational control during spermatogenesis. The knowledge gained from these studies may be useful in the genetic assessment of male infertility in humans, and lead to the development of male contraceptives designed to disrupt essential regulatory steps during normal spermatogenesis. Our studies will focus on the regulation of the spermatid-specific protamine mRNAs. Transgenesis will be used to test specific models for the function of previously identified regulatory sequences in the protamine I, Prm1, 3' untranslated region. A screen will be performed to identify new genes that regulate the translational repression of Prm1 in round spermatids. Mutation of the Prbp gene results in defects in the translational activation of the protamine mRNAs in elongated spermatids and cause male sterility. DNA arrays will be screened to determine the specificity of the Prbp mutant phenotype. Several approaches will be used to pursue the role of PRBP in translational activation. Lastly, targeted mutagenesis will be used to investigate the function of murine Y box proteins in posttranscriptional control.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027215-14
Application #
6696279
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Taymans, Susan
Project Start
1990-09-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2006-01-31
Support Year
14
Fiscal Year
2004
Total Cost
$303,816
Indirect Cost
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Snyder, Elizabeth; Soundararajan, Ramani; Sharma, Manju et al. (2015) Compound Heterozygosity for Y Box Proteins Causes Sterility Due to Loss of Translational Repression. PLoS Genet 11:e1005690
Greenlee, Anne R; Shiao, Meng-Shin; Snyder, Elizabeth et al. (2012) Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1. PLoS One 7:e46359
Kaneko, Hiroki; Dridi, Sami; Tarallo, Valeria et al. (2011) DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471:325-30
Daher, Aicha; Laraki, Ghislaine; Singh, Madhurima et al. (2009) TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress. Mol Cell Biol 29:254-65
Sadate-Ngatchou, Patricia I; Payne, Christopher J; Dearth, Andrea T et al. (2008) Cre recombinase activity specific to postnatal, premeiotic male germ cells in transgenic mice. Genesis 46:738-42
Connolly, Charles M; Dearth, Andrea T; Braun, Robert E (2005) Disruption of murine Tenr results in teratospermia and male infertility. Dev Biol 278:13-21
Giorgini, Flaviano; Davies, Holly G; Braun, Robert E (2002) Translational repression by MSY4 inhibits spermatid differentiation in mice. Development 129:3669-79
Zhong, J; Peters, A H; Kafer, K et al. (2001) A highly conserved sequence essential for translational repression of the protamine 1 messenger rna in murine spermatids. Biol Reprod 64:1784-9
Giorgini, F; Davies, H G; Braun, R E (2001) MSY2 and MSY4 bind a conserved sequence in the 3' untranslated region of protamine 1 mRNA in vitro and in vivo. Mol Cell Biol 21:7010-9
Nadler, J J; Braun, R E (2000) Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells. Genesis 27:117-23

Showing the most recent 10 out of 22 publications