TY - JOUR
T1 - The E3 ubiquitin ligase Cullin 4A regulates meiotic progression in mouse spermatogenesis
AU - Yin, Yan
AU - Lin, Congxing
AU - Kim, Sung Tae
AU - Roig, Ignasi
AU - Chen, Hong
AU - Liu, Liren
AU - Veith, George Michael
AU - Jin, Ramon U.
AU - Keeney, Scott
AU - Jasin, Maria
AU - Moley, Kelle
AU - Zhou, Pengbo
AU - Ma, Liang
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - The Cullin-RING ubiquitin-ligase CRL4 controls cell cycle and DNA damage checkpoint response and ensures genomic integrity. Inactivation of the Cul4 component of the CRL4 E3 ligase complex in Caenorhabditis elegans by RNA interference results in massive mitotic DNA re-replication in the blast cells, largely due to failed degradation of the DNA licensing protein, CDT-1, and premature spermatogenesis. Here we show that inactivation of Cul4a by gene-targeting in mice only affected male but not female fertility. This male infertility phenotype resulted from a combination of decreased spermatozoa number, reduced sperm motility and defective acrosome formation. Agenesis of the mutant germ cells was accompanied by increased cell death in pachytene/diplotene cells with markedly elevated levels of phospho-p53 and CDT-1. Despite apparent normal assembly of synaptonemal complexes and DNA double strand break repair, dissociation of MLH1, a component of the late recombination nodule, was delayed in Cul4a-/- diplotene spermatocytes, which potentially led to subsequent disruptions in meiosis II and spermiogenesis. Together, our study revealed an indispensable role for Cul4a during male germ cell meiosis.
AB - The Cullin-RING ubiquitin-ligase CRL4 controls cell cycle and DNA damage checkpoint response and ensures genomic integrity. Inactivation of the Cul4 component of the CRL4 E3 ligase complex in Caenorhabditis elegans by RNA interference results in massive mitotic DNA re-replication in the blast cells, largely due to failed degradation of the DNA licensing protein, CDT-1, and premature spermatogenesis. Here we show that inactivation of Cul4a by gene-targeting in mice only affected male but not female fertility. This male infertility phenotype resulted from a combination of decreased spermatozoa number, reduced sperm motility and defective acrosome formation. Agenesis of the mutant germ cells was accompanied by increased cell death in pachytene/diplotene cells with markedly elevated levels of phospho-p53 and CDT-1. Despite apparent normal assembly of synaptonemal complexes and DNA double strand break repair, dissociation of MLH1, a component of the late recombination nodule, was delayed in Cul4a-/- diplotene spermatocytes, which potentially led to subsequent disruptions in meiosis II and spermiogenesis. Together, our study revealed an indispensable role for Cul4a during male germ cell meiosis.
KW - Cullin4
KW - Meiosis
KW - Mlh1
UR - http://www.scopus.com/inward/record.url?scp=79959865171&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2011.05.661
DO - 10.1016/j.ydbio.2011.05.661
M3 - Article
C2 - 21624359
AN - SCOPUS:79959865171
VL - 356
SP - 51
EP - 62
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 1
ER -