Conditional inactivation of Miwi2 reveals that MIWI2 is only essential for prospermatogonial development in mice.
The PIWI-piRNA pathway serves as a critical defense mechanism through which the genome of the male germline is protected from invasion by transposable elements (TEs). MIWI2/PIWIL4, a member of the murine PIWI subclade of the Argonaute family, has been shown to be expressed in primordial germ cells (PGCs) and prospermatogonia in fetal and prepubertal testes. Global inactivation of Miwi2 leads to male sterility due to an early meiotic arrest, which correlates with retrotransposon desuppression. However, it remains unclear whether MIWI2 functions beyond the PGC stage and whether MIWI2 has a role beyond TE suppression during male germ line development. Through conditional inactivation of Miwi2, we demonstrate herein that MIWI2 function is restricted to a narrow time window during male PGC reprograming and that Miwi2 is dispensable for postnatal male germline development and testicular function in mice. Moreover, persistent activation of LINE1 and IAP retrotransposons caused by Miwi2 inactivation is compatible with mitotic cell cycle progression of spermatogonia during the first wave of spermatogenesis, but can cause zygotene to pachytene arrest in early meiosis due to multiple defects including enhanced DNA double-strand breaks, aberrant histone modifications and altered mRNA transcriptome. Our data not only validate those from global Miwi2 KO studies, but also suggest that MIWI2 and MIWI2-associated piRNAs have functions beyond TE suppression.
Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, 1664 North Virginia Street, Mailstop 0575, Reno, NV 89557, USA.
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0000000312482687
J
Bao
Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, 1664 North Virginia Street, Mailstop 0575, Reno, NV 89557, USA.
Y
Y
Zhang
Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, 1664 North Virginia Street, Mailstop 0575, Reno, NV 89557, USA.
A S
AS
Schuster
Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, 1664 North Virginia Street, Mailstop 0575, Reno, NV 89557, USA.
N
N
Ortogero
Washington State University, Abelson Hall Room 507, Pullman, WA 99164, USA.
E E
EE
Nilsson
Washington State University, Abelson Hall Room 507, Pullman, WA 99164, USA.
M K
MK
Skinner
Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, 1664 North Virginia Street, Mailstop 0575, Reno, NV 89557, USA.
W
W
Yan
D000818:Animals; D060565:Argonaute Proteins / Q000172:deficiency / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004251:DNA Transposable Elements / Q000235:genetics; D020868:Gene Silencing; D005854:Germ Cells; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000166:cytology / Q000502:physiology; D013737:Testis / Q000502:physiology*
D060565:Argonaute Proteins; D004251:DNA Transposable Elements; C546575:PIWIL4 protein, mouse; D034741:RNA, Small Interfering