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Cell Rep. 2018 Jul 3;24(1):79-94. doi: 10.1016/j.celrep.2018.06.010.

Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain.

Author information

1
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
2
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan.
3
Department of Anatomy, Toho University, Tokyo 143-8540, Japan.
4
Department of Immunology, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
5
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
6
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan; Department of Developmental and Regenerative Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
7
Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
8
Department of Genetic and Behavioral Neuroscience, Gunma University, Maebashi 371-8511, Japan.
9
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
10
Department of Genome Biology, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
11
Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan.
12
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Anatomy, Toho University, Tokyo 143-8540, Japan. Electronic address: funato.hiromasa.km@u.tsukuba.ac.jp.
13
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan. Electronic address: hoshino@ncnp.go.jp.

Abstract

The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain.

KEYWORDS:

Ptf1a; central nervous system; hypothalamus; kisspeptin; sexual behavior; sexual differentiation

PMID:
29972793
DOI:
10.1016/j.celrep.2018.06.010
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