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.
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.
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