TY - JOUR
T1 - Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development
AU - Fujimoto, Yuka
AU - Tanaka, Satomi S.
AU - Yamaguchi, Yasuka L.
AU - Kobayashi, Hiroki
AU - Kuroki, Shunsuke
AU - Tachibana, Makoto
AU - Shinomura, Mai
AU - Kanai, Yoshiakira
AU - Morohashi, Ken ichirou
AU - Kawakami, Kiyoshi
AU - Nishinakamura, Ryuichi
N1 - Funding Information:
We thank Robin Lovell-Badge, Peter Koopman, Richard Behringer, and Patrick Tam for their helpful suggestions and comments, Peter Koopman for the Sox9 probe, Richard Behringer for the Mis probe, and Maho Kumagai, Jyunko Nakai, Tomoko Ohmori, Takeshi Terabayashi, and Atsuhiro Taguchi for their technical assistance and support. This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society for the Promotion of Science, and a scholarship from the Graduate School of Medical Sciences, Kumamoto University, Japan.
PY - 2013/8/26
Y1 - 2013/8/26
N2 - The Y-linked gene Sry regulates mammalian sex determination in bipotential embryonic gonads. Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation. Loss of Six1 and Six4 together, but neither alone, resulted in a male-to-female sex-reversal phenotype in XY mutant gonads accompanied by a failure in Sry activation. Decreased gonadal precursor cell formation at the onset of Sry expression and a gonadal size reduction in both sexes were also found in mutant embryos. Forced Sry transgene expression in XY mutant gonads rescued testicular development but not the initial disruption to precursor growth. Furthermore, we identified two downstream targets of Six1/Six4 in gonadal development, Fog2 (Zfpm2) and Nr5a1 (Ad4BP/Sf1). These two distinct Six1/Six4-regulated pathways are considered to be crucial for gonadal development. The regulation of Fog2 induces Sry expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size.
AB - The Y-linked gene Sry regulates mammalian sex determination in bipotential embryonic gonads. Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation. Loss of Six1 and Six4 together, but neither alone, resulted in a male-to-female sex-reversal phenotype in XY mutant gonads accompanied by a failure in Sry activation. Decreased gonadal precursor cell formation at the onset of Sry expression and a gonadal size reduction in both sexes were also found in mutant embryos. Forced Sry transgene expression in XY mutant gonads rescued testicular development but not the initial disruption to precursor growth. Furthermore, we identified two downstream targets of Six1/Six4 in gonadal development, Fog2 (Zfpm2) and Nr5a1 (Ad4BP/Sf1). These two distinct Six1/Six4-regulated pathways are considered to be crucial for gonadal development. The regulation of Fog2 induces Sry expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size.
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U2 - 10.1016/j.devcel.2013.06.018
DO - 10.1016/j.devcel.2013.06.018
M3 - Article
C2 - 23987514
AN - SCOPUS:84883044240
VL - 26
SP - 416
EP - 430
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 4
ER -