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 #
1R21HD071736-01A1
Application #
8401509
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
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$246,545
Indirect Cost
$71,545
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Zhang, Ying; Tang, Chong; Yu, Tian et al. (2017) MicroRNAs control mRNA fate by compartmentalization based on 3' UTR length in male germ cells. Genome Biol 18:105
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; Vitting-Seerup, Kristoffer; Waage, Johannes et al. (2016) UPF2-Dependent Nonsense-Mediated mRNA Decay Pathway Is Essential for Spermatogenesis by Selectively Eliminating Longer 3'UTR Transcripts. PLoS Genet 12:e1005863
Schuster, Andrew; Tang, Chong; Xie, Yeming et al. (2016) SpermBase: A Database for Sperm-Borne RNA Contents. Biol Reprod 95:99
Fededa, Juan Pablo; Esk, Christopher; Mierzwa, Beata et al. (2016) MicroRNA-34/449 controls mitotic spindle orientation during mammalian cortex development. EMBO J 35:2386-2398
Yuan, Shuiqiao; Tang, Chong; Schuster, Andrew et al. (2016) Paternal pachytene piRNAs are not required for fertilization, embryonic development and sperm-mediated epigenetic inheritance in mice. Environ Epigenet 2:
Chen, Qi; Yan, Wei; Duan, Enkui (2016) Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet 17:733-743
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
Yuan, Shuiqiao; Tang, Chong; Zhang, Ying et al. (2015) mir-34b/c and mir-449a/b/c are required for spermatogenesis, but not for the first cleavage division in mice. Biol Open 4:212-23
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

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