It is well known that both mouse and human sperm carry numerous messenger RNAs and small non-coding RNAs into eggs during fertilization. Are these paternal RNAs essential for fertilization and early embryonic development? If so, what do these sperm-borne RNA molecules do once inside the cytoplasm of the egg? Theses fundamental questions remain unanswered because these RNA molecules are hidden deeply inside the highly compacted sperm chromatin. Thus, these sperm- borne RNA species are almost totally inaccessible without disrupting paternal DNA. We have generated two conditional knockout mouse lines, which produce sperm lacking miRNAs and/or endo-siRNAs. We will use these small non-coding RNA- deficient sperm to perform intracytoplasmic sperm injection (ICSI) to observe the fertilization rate and early embryonic development (Aim2). The RNA contents in these small RNA-deficient sperm will also be defined in comparison to those in normal wild-type sperm (Aim1). A negative finding would suggest that at least these two sperm-borne small non-coding RNA species are dispensable for fertilization and/or early embryonic development. However, if these two small RNA species are found to be essential for fertilization and/or embryonic development, then a more thorough study is warranted because the paternal contribution to fertilization or even early embryonic development has been hypothesized for a long time and it represents one of the most fundamental questions about factors that are required for the beginning of a life. Therefore, this exploratory study fits the high risk, high reward philosophy of the R2 funding mechanism.

Public Health Relevance

The study will test whether two of the sperm-;borne small RNA species are required for fertilization and early embryonic development. Data from this study will potentially lead to discoveries of novel factors that are responsble for infertility, spontaneous abortion and birth defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD071736-02
Application #
8514666
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (04))
Program Officer
Moss, Stuart B
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$133,712
Indirect Cost
$38,812
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Yuan, Shuiqiao; Schuster, Andrew; Tang, Chong et al. (2016) Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development 143:635-47
Bao, Jianqiang; Tang, Chong; Yuan, Shuiqiao et al. (2015) UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome. Development 142:352-62
Ortogero, Nicole; Hennig, Grant W; Luong, Dickson et al. (2015) Computer-assisted annotation of small RNA transcriptomes. Methods Mol Biol 1218:353-64
Yuan, Shuiqiao; Qin, Weibing; Riordan, Connor R et al. (2015) Ubqln3, a testis-specific gene, is dispensable for embryonic development and spermatogenesis in mice. Mol Reprod Dev 82:266-7
Oliver, Daniel; Yuan, Shuiqiao; McSwiggin, Hayden et al. (2015) Pervasive Genotypic Mosaicism in Founder Mice Derived from Genome Editing through Pronuclear Injection. PLoS One 10:e0129457
Yuan, Shuiqiao; Swiggin, Hayden M C; Zheng, Huili et al. (2015) A testis-specific gene, Ubqlnl, is dispensable for mouse embryonic development and spermatogenesis. Mol Reprod Dev 82:408-9
Wu, Jingwen; Bao, Jianqiang; Kim, Minkyung et al. (2014) Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc Natl Acad Sci U S A 111:E2851-7
Bao, J; Zhang, Y; Schuster, A S et al. (2014) Conditional inactivation of Miwi2 reveals that MIWI2 is only essential for prospermatogonial development in mice. Cell Death Differ 21:783-96
Ortogero, Nicole; Schuster, Andrew S; Oliver, Daniel K et al. (2014) A novel class of somatic small RNAs similar to germ cell pachytene PIWI-interacting small RNAs. J Biol Chem 289:32824-34
Bao, Jianqiang; Tang, Chong; Li, Jiachen et al. (2014) RAN-binding protein 9 is involved in alternative splicing and is critical for male germ cell development and male fertility. PLoS Genet 10:e1004825

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