The long-term objective of the current application is to elucidate the biogenesis and function of a novel class of small non-coding RNAs, the piRNAs. RNA interference has emerged as a major regulatory mechanism in gene silencing in which small non-coding RNAs function as sequence-specific guides. MicroRNAs, a relatively well- characterized class of small non-coding RNAs, are essential for normal development and are implicated in many human diseases. In contrast, the biogenesis and function of piRNAs (Piwi-interacting RNAs), a diverse class of germline-specific small non-coding RNAs, is poorly understood. Recent studies in diverse organisms including fly, zebra fish, and mice have shown that Piwi proteins and piRNAs are required for silencing of transposable elements in the germline. We have found that MOV10L1, a putative RNA helicase, binds to all Piwi proteins and is an essential component of the piRNA pathway. Therefore, MOV10L1 is the only known master regulator of the mammalian piRNA pathway. Disruption of Mov10l1 leads to a loss of piRNAs and meiotic arrest in males. Using our unique Mov10l1 conditional mutant and other genetic models, we plan to: 1) investigate the chromatin integrity and functional competency of MOV10L1/piRNA-deficient round spermatids, 2) elucidate the role of MOV10L1 in the biogenesis and function of pachytene piRNAs, and 3) biochemically characterize the role of the MOV10L1 homologue in piRNA biogenesis in cultured silkworm (Bombyx mori) BmN4 ovarian cell lines. These studies will elucidate the mechanistic basis of piRNA biogenesis and a novel function for MOV10L1 and pachytene piRNAs in maintaining genome integrity during spermiogenesis. These studies will provide insight into etiology, diagnosis, and prevention of human diseases including male infertility and birth defects.

Public Health Relevance

piRNAs are a novel class of small non-coding RNAs. Understanding their function in maintaining genome integrity in the germline will provide insight into the etiology, diagnosis, and prevention of human diseases such as male infertility, pregnancy loss, and birth defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD069592-02
Application #
8462286
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2012-05-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$283,941
Indirect Cost
$91,104
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cora, Elisa; Pandey, Radha R; Xiol, Jordi et al. (2014) The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs. RNA 20:773-81