TAp73 is required for spermatogenesis and the maintenance of male fertility.
The generation of viable sperm proceeds through a series of coordinated steps, including germ cell self-renewal, meiotic recombination, and terminal differentiation into functional spermatozoa. The p53 family of transcription factors, including p53, p63, and p73, are critical for many physiological processes, including female fertility, but little is known about their functions in spermatogenesis. Here, we report that deficiency of the TAp73 isoform, but not p53 or ΔNp73, results in male infertility because of severe impairment of spermatogenesis. Mice lacking TAp73 exhibited increased DNA damage and cell death in spermatogonia, disorganized apical ectoplasmic specialization, malformed spermatids, and marked hyperspermia. We demonstrated that TAp73 regulates the mRNA levels of crucial genes involved in germ stem/progenitor cells (CDKN2B), spermatid maturation/spermiogenesis (metalloproteinase and serine proteinase inhibitors), and steroidogenesis (CYP21A2 and progesterone receptor). These alterations of testicular histology and gene expression patterns were specific to TAp73 null mice and not features of mice lacking p53. Our work provides previously unidentified in vivo evidence that TAp73 has a unique role in spermatogenesis that ensures the maintenance of mitotic cells and normal spermiogenesis. These results may have implications for the diagnosis and management of human male infertility.
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
Satoshi
S
Inoue
Richard
R
Tomasini
Alessandro
A
Rufini
Andrew J
AJ
Elia
Massimiliano
M
Agostini
Ivano
I
Amelio
Dave
D
Cescon
David
D
Dinsdale
Lily
L
Zhou
Isaac S
IS
Harris
Sophie
S
Lac
Jennifer
J
Silvester
Wanda Y
WY
Li
Masato
M
Sasaki
Jillian
J
Haight
Anne
A
Brüstle
Andrew
A
Wakeham
Colin
C
McKerlie
Andrea
A
Jurisicova
Gerry
G
Melino
Tak W
TW
Mak
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002452:Cell Count; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007248:Infertility, Male / Q000097:blood / Q000235:genetics / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011374:Progesterone / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D011374:Progesterone; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
ADAM17; MMP13; Serpin; Timp