In a new study conducted at the University of Hawai\u02bbi at M\u0101noa, researchers from the John A. Burns School of Medicine (JABSOM) have shown that the loss of a key male fertility gene leads to infertility and changes expression of hundreds of other important genes.<\/p>\n
The study was led by Professor Dr. Monika Ward from the Department of Anatomy, Biochemistry & Physiology and the Yanagimachi Institute for Biogenesis Research (YIBR). The team has been investigating a zinc finger Y-encoded gene called\u00a0Zfy. This gene, encoded on Y chromosome in both mice and humans, is considered a male fertility factor. In mice,\u00a0Zfy\u00a0is present as two copies, Zfy1 and Zfy2.<\/p>\n
The researchers first used CRISPR-Cas9 to produce knockout mice specifically lacking\u00a0Zfy1,\u00a0Zfy2, and both\u00a0Zfy1\u00a0and\u00a0Zfy2\u00a0genes, the latter called\u00a0Zfy\u00a0DKO (Zfy\u00a0double knockout). They observed that\u00a0Zfy\u00a0DKO males were completely infertile and had severely abnormal sperm. In the most severe cases,\u00a0Zfy\u00a0DKO males could not produce sperm at all. These findings were published in 2022, in\u00a0Biology of Reproduction.\u00a0<\/p>\n
The team then applied assisted reproduction technologies (ART) to produce more infertile\u00a0Zfy\u00a0DKO males so that investigations of these mice can continue. They used intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) \u2013 techniques pioneered at the University of Hawai\u02bbi by the YIBR founder, Ryuzo Yanagimachi. In the new study, published on August 27 in\u00a0Cell Death and Differentiation, the team shows the molecular consequences of\u00a0Zfy\u00a0loss.<\/p>\n
The researchers demonstrated that without\u00a0Zfy\u00a0hundreds of genes become deregulated, expressed either too strongly or too weak. Among these genes are those responsible for sperm production, for DNA packaging and organization, and for cell death. The team linked deregulation of these genes to changes in testes and sperm. They found that sperm precursor cells in the testes were dying prematurely and sperm, if produced, had DNA that was not properly condensed and as such vulnerable to damage.<\/p>\n
This work really pushes forward our understanding of how this important Zfy\u00a0gene works. We identified pathways and other genes that are affected and we can now study how exactly\u00a0Zfy regulates them.”<\/p>\n
Dr. Monika Ward, Professor, Department of Anatomy, Biochemistry & Physiology and the Yanagimachi Institute for Biogenesis Research (YIBR)<\/p>\n
“This study exemplifies a critical role undergraduate and graduate students play in research at the University of Hawai\u02bbi. The first author of the paper, and a person who performed most of the work, is a recently graduated PhD student in the Developmental and Reproductive Biology (DRB) graduate program, Hayden Holmlund. Hayden now continues his academic career as a post-doctoral fellow in California. Some of the experiments were performed by an undergraduate INBRE student, Benazir Yarbabaeva, who has just started as a MS student in DRB program to continue her explorations of\u00a0Zfy\u00a0DKO sperm”, continued Dr. Ward.<\/p>\n
“Finally, the study exemplifies the core mission of the YIBR.” said Dr. Ward. The YIBR fosters collaboration in reproductive and developmental biology and beyond. “The new study was performed with contributions from colleagues from France and England”<\/p>\n
The study represents a significant step forward in our understanding of how male fertility is regulated and opens the path for future explorations of\u00a0Zfy regulatory role in sperm production. The fundamental knowledge obtained through basic research using mice as a model addresses a specific health need – management of male fertility\/treatment of male infertility – and has translational implications.<\/p>\n
Source:<\/p>\n
University of Hawaii at Manoa<\/a><\/p>\n Journal reference:<\/p>\n