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LETTERSOligo-astheno-teratozoospermia in mice lacking Cnot7,
a regulator of retinoid X receptor beta.com/naturegeneticsTakahisa Nakamura1, Ryoji Yao2, Takehiko Ogawa3, Toru Suzuki1, Chizuru Ito4, Naoki Tsunekawa5,
Kimiko Inoue6, Rieko Ajima1, Takashi Miyasaka1, Yutaka Yoshida1, Atsuo Ogura6, Kiyotaka Toshimori4,
Toshiaki Noce5, Tadashi Yamamoto1 & Tetsuo Noda2,7,8http://www.natureSpermatogenesis is a complex process that involves cooperation
of germ cells and testicular somatic cells. Various genetic
disorders lead to impaired spermatogenesis, defective sperm
function and male infertility1. Here we show that Cnot7/ males
are sterile owing to oligo-astheno-teratozoospermia, suggesting
that Cnot7, a CCR4-associated transcriptional cofactor2, is
essential for spermatogenesis. Maturation of spermatids is
unsynchronized and impaired in seminiferous tubules ofCnot7/ mice. Transplantation of spermatogonial stem cells
from male Cnot7/ mice to seminiferous tubules of Kit mutant
mice (KitW/W-v) restores spermatogenesis, suggesting that the
function of testicular somatic cells is damaged in the Cnot7/
condition. The testicular phenotypes of Cnot7/ mice are
similar to those of mice deficient in retinoid X receptor beta(Rxrb)3. We further show that Cnot7 binds the AF-1 domain of
Rxrb and that Rxrb malfunctions in the absence of Cnot7.
Therefore, Cnot7 seems to function as a coregulator of Rxrb in
testicular somatic cells and is thus involved in spermatogenesis.Genetic analyses in yeast suggest that CAF1, a component of the CCR4-
NOT complex, has multiple roles in regulating transcription4. In addition, proteins in the CCR4-NOT complex are involved in mRNA
metabolism in yeast5,6. Two mammalian homologs of yeast CAF1 are
known: Cnot7 (also called CAF1) and Cnot8 (also called CALIF)7,8.
Both are expressed in a variety of tissues, with relatively high expression
of Cnot7 in lung, liver and thyroid gland7,8. Cnot7 interacts with members of the TOB-BTG antiproliferative family, which comprises Tob1,
Tob2, Btg1, Btg2 (also called PC3 and TIS21), Btg3 (also called ANA)
and Btg4 (also called PC3B; refs. 7,9,10). The proteins of this family are
implicated in regulation of transcription1114.To elucidate the physiological role of mammalian Cnot7, we produced mutant mice lacking the gene Cnot7 by means of homologous
recombination (Fig. 1ad). Homozygous Cnot7 knockout (Cnot7/)
mice were alive at birth and born at the predicted mendelian frequency. Adult Cnot7/ mice had normal health, size and behavior,
except that male Cnot7/ mice were sterile. Cnot7+/ males had normal fertility and Cnot7/ females produced average-size litters (6.3 2.1 offspring per...