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16 March 2022 Loss of mouse Y chromosome gene Zfy1 and Zfy2 leads to spermatogenesis impairment, sperm defects, and infertility
Yasuhiro Yamauchi, Takafumi Matsumura, Jackson Bakse, Hayden Holmlund, Genevieve Blanchet, Emmaelle Carrot, Masahito Ikawa, Monika A. Ward
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Abstract

Using mice with Y chromosome deficiencies and supplementing Zfy transgenes, we, and others, have previously shown that the loss of Y chromosome Zfy1 and Zfy2 genes is associated with infertility and spermiogenic defects and that the addition of Zfy transgenes rescues these defects. In these past studies, the absence of Zfy was linked to the loss of other Y chromosome genes, which might have contributed to spermiogenic phenotypes. Here, we used CRISPR/Cas9 to specifically remove open reading frame of Zfy1, Zfy2, or both Zfy1 and Zfy2, and generated Zfy knockout (KO) and double knockout (DKO) mice. Zfy1 KO and Zfy2 KO mice were both fertile, but the latter had decreased litters size and sperm number, and sperm headshape abnormalities. Zfy DKO males were infertile and displayed severe spermatogenesis defects. Postmeiotic arrest largely prevented production of sperm and the few sperm that were produced all displayed gross headshape abnormalities and structural defects within head and tail. Infertility of Zfy DKO mice could be overcome by injection of spermatids or sperm directly to oocytes, and the resulting male offspring had the same spermiogenic phenotype as their fathers. The study is the first describing detailed phenotypic characterization of mice with the complete Zfy gene loss. It provides evidence supporting that the presence of at least one Zfy homolog is essential for male fertility and development of normal sperm functional in unassisted fertilization. The data also show that while the loss of Zfy1 is benign, the loss of Zfy2 is mildly detrimental for spermatogenesis.

Summary Sentence

Mice with a complete loss of Y chromosome encoded Zfy1 and Zfy2 genes generated by CRISPR/Cas9-mediated open reading frame knockout are infertile and display severe spermatogenesis and sperm defects.

© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Yasuhiro Yamauchi, Takafumi Matsumura, Jackson Bakse, Hayden Holmlund, Genevieve Blanchet, Emmaelle Carrot, Masahito Ikawa, and Monika A. Ward "Loss of mouse Y chromosome gene Zfy1 and Zfy2 leads to spermatogenesis impairment, sperm defects, and infertility," Biology of Reproduction 106(6), 1312-1326, (16 March 2022). https://doi.org/10.1093/biolre/ioac057
Received: 16 December 2021; Accepted: 11 March 2022; Published: 16 March 2022
JOURNAL ARTICLE
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KEYWORDS
assisted reproduction
CRISPR/Cas9
Male infertility
sperm
spermatogenesis
testis
Y CHROMOSOME
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