News | University of Hawaiʻi Study Finds Loss of Key Y-Chromosome Genes Causes Infertility in Male Mice and Alters Hundreds of Genes
Researchers at the University of Hawaiʻi at Mānoa John A. Burns School of Medicine (JABSOM) found that loss of a key Y-chromosome gene causes complete infertility in male mice and abnormal expression of hundreds of important genes.
Led by Dr. Monika Ward, Professor in the Department of Anatomy, Biochemistry and Physiology and the Yanagimachi Institute for Biogenesis Research (YIBR), the team studied the Zinc finger Y-encoded gene Zfy. Present in humans and mice, Zfy is considered an important regulator of male reproduction. Mice have two copies, Zfy1 and Zfy2.
Using CRISPR-Cas9, researchers created mice lacking Zfy1, Zfy2, or both, called Zfy double-knockout (Zfy DKO) mice. Zfy DKO males were completely infertile and had severe sperm abnormalities; in extreme cases, they produced no sperm. Initial findings were published in Biology of Reproduction in 2022.
To study the molecular mechanism further, the team used assisted reproductive techniques pioneered by YIBR founder Ryuzo Yanagimachi, including intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI), to produce more infertile Zfy DKO males. Recent results were published in Cell Death and Differentiation on August 27, 2025.
Without Zfy, hundreds of genes were dysregulated, including genes controlling sperm formation, DNA packaging and conformation, and apoptosis. Sperm precursor cells in the testes died prematurely, and any sperm produced had poorly condensed, easily damaged DNA.
“This study greatly advances our understanding of Zfy function. We identified affected signaling pathways and genes and will next explore how Zfy regulates these key processes,” Dr. Ward said.
Dr. Ward highlighted the central role of University of Hawaiʻi students. First author Hayden Holmlund, who performed most experiments, recently graduated from the Developmental and Reproductive Biology (DRB) doctoral program and is now a postdoctoral researcher in California. Undergraduate INBRE student Benazir Yarbabaeva performed some experiments and has joined DRB as a master’s student to continue investigating Zfy DKO sperm.
“The study also reflects YIBR’s mission to advance international collaboration in reproductive and developmental biology,” Dr. Ward added, noting contributions from researchers in France and the United Kingdom.
The study advances understanding of male fertility regulation and establishes a basis for future research into Zfy’s role in spermatogenesis. Knowledge from mouse models is important for understanding male infertility mechanisms and may inform translational research into potential treatments.
News | University of Hawaiʻi Study Finds Loss of Key Y-Chromosome Genes Causes Infertility in Male Mice and Alters Hundreds of Genes
News | University of Hawaiʻi Study Finds Loss of Key Y-Chromosome Genes Causes Infertility in Male Mice and Alters Hundreds of Genes
Researchers at the University of Hawaiʻi at Mānoa John A. Burns School of Medicine (JABSOM) found that loss of a key Y-chromosome gene causes complete infertility in male mice and abnormal expression of hundreds of important genes.
Led by Dr. Monika Ward, Professor in the Department of Anatomy, Biochemistry and Physiology and the Yanagimachi Institute for Biogenesis Research (YIBR), the team studied the Zinc finger Y-encoded gene Zfy. Present in humans and mice, Zfy is considered an important regulator of male reproduction. Mice have two copies, Zfy1 and Zfy2.
Using CRISPR-Cas9, researchers created mice lacking Zfy1, Zfy2, or both, called Zfy double-knockout (Zfy DKO) mice. Zfy DKO males were completely infertile and had severe sperm abnormalities; in extreme cases, they produced no sperm. Initial findings were published in Biology of Reproduction in 2022.
To study the molecular mechanism further, the team used assisted reproductive techniques pioneered by YIBR founder Ryuzo Yanagimachi, including intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI), to produce more infertile Zfy DKO males. Recent results were published in Cell Death and Differentiation on August 27, 2025.
Without Zfy, hundreds of genes were dysregulated, including genes controlling sperm formation, DNA packaging and conformation, and apoptosis. Sperm precursor cells in the testes died prematurely, and any sperm produced had poorly condensed, easily damaged DNA.
“This study greatly advances our understanding of Zfy function. We identified affected signaling pathways and genes and will next explore how Zfy regulates these key processes,” Dr. Ward said.
Dr. Ward highlighted the central role of University of Hawaiʻi students. First author Hayden Holmlund, who performed most experiments, recently graduated from the Developmental and Reproductive Biology (DRB) doctoral program and is now a postdoctoral researcher in California. Undergraduate INBRE student Benazir Yarbabaeva performed some experiments and has joined DRB as a master’s student to continue investigating Zfy DKO sperm.
“The study also reflects YIBR’s mission to advance international collaboration in reproductive and developmental biology,” Dr. Ward added, noting contributions from researchers in France and the United Kingdom.
The study advances understanding of male fertility regulation and establishes a basis for future research into Zfy’s role in spermatogenesis. Knowledge from mouse models is important for understanding male infertility mechanisms and may inform translational research into potential treatments.
Source:
Collected online