Spermiogenesis, the process by which postmeiotic round spermatids differentiate into elongated spermatozoa, entails a remarkable series of morphological and molecular events. This proposal seeks funding to study a mouse ReproGenomics mutation (repro5) that has the unique effect of causing both male and female infertility from defects that occur after the meiotic prophase I events that are common to both sexes. Mutant males produce low numbers of sperm characterized by poor motility, abnormal morphology and nonviability. Oocytes from mutant females are morphologically normal, but are unable to initiate embryonic development following sperm penetration. Positional cloning identified a mutation in Brwd1 (Bromodomain and WD domain containing 1), a broadly expressed gene with putative transcriptional regulator activity. Brwd1 is believed to act on chromatin through interactions with the Brg1-dependent SWI/SNF chromatin-remodeling pathway. As a bromodomain containing protein, it potentially interacts with hyperacetylated histone lysine residues, a characteristic of sperm chromatin in early Spermiogenesis before eventual replacement of histones by the protamines. In this project we will test three hypotheses regarding the function of BRWD1 in Spermiogenesis: 1) that it regulates the postmeiotic expression of key genes before transcription ceases in late Spermiogenesis; 2) that it is necessary for chromatin remodeling and compaction for purposes of packaging into the sperm head; and 3) that it functions in post-transcriptional gene regulation. In conjunction with Project III, these studies will illuminate the molecular relationship between the infertility phenotypes in both sexes. Additionally, we will investigate the roles of two Brwd1 paralogs in the mouse genome, Brwd3 and Phip, to determine if they have distinct or overlapping roles in gametogenesis and/or development.

Public Health Relevance

Reduced sperm quantity, quality and/or motility are primary causes of male human infertility. This project utilizes a strain of laboratory mice with such defects to understanding a major process required for normal sperm production: proper restructuring and processing of the DNA so as to allow fertilization of the egg. These experiments should yield insight into the causes of human sperm defects, and potentially, how they can be remediated safely.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD042137-10
Application #
8380515
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$161,239
Indirect Cost
$51,029
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Hays, E; Majchrzak, N; Daniel, V et al. (2017) Spermatogenesis associated 22 is required for DNA repair and synapsis of homologous chromosomes in mouse germ cells. Andrology 5:299-312
Fujiwara, Yasuhiro; Matsumoto, Hirokazu; Akiyama, Kouyou et al. (2015) An ENU-induced mutation in the mouse Rnf212 gene is associated with male meiotic failure and infertility. Reproduction 149:67-74
Sun, Fengyun; Fujiwara, Yasuhiro; Reinholdt, Laura G et al. (2015) Nuclear localization of PRDM9 and its role in meiotic chromatin modifications and homologous synapsis. Chromosoma 124:397-415
Pattabiraman, Shrivatsav; Baumann, Claudia; Guisado, Daniela et al. (2015) Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. J Cell Biol 208:53-69
Harris, Tanya P; Schimenti, Kerry J; Munroe, Robert J et al. (2014) IQ motif-containing G (Iqcg) is required for mouse spermiogenesis. G3 (Bethesda) 4:367-72
Li, Xin Zhiguo; Roy, Christian K; Dong, Xianjun et al. (2013) An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Mol Cell 50:67-81
Schimenti, Kerry J; Feuer, Sky K; Griffin, Laurie B et al. (2013) AKAP9 is essential for spermatogenesis and sertoli cell maturation in mice. Genetics 194:447-57
Liu, Ye; Zaun, Hans C; Orlowski, John et al. (2013) CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. J Neurosci 33:12656-69
Fujiwara, Yasuhiro; Ogonuki, Narumi; Inoue, Kimiko et al. (2013) t-SNARE Syntaxin2 (STX2) is implicated in intracellular transport of sulfoglycolipids during meiotic prophase in mouse spermatogenesis. Biol Reprod 88:141
Gómez, Rocío; Jordan, Philip W; Viera, Alberto et al. (2013) Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis suggests functions in distinct chromosome processes. J Cell Sci 126:4239-52

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