Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation
Hideki Ando,
Tomomi Sato,
Takumi Ito,
Junichi Yamamoto,
Satoshi Sakamoto,
Nobuhiro Nitta,
Tomoko Asatsuma-Okumura,
Nobuyuki Shimizu,
Ryota Mizushima,
Ichio Aoki,
Takeshi Imai,
Yuki Yamaguchi,
Arnold J. Berk,
Hiroshi Handa
Affiliations
Hideki Ando
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Tomomi Sato
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Takumi Ito
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan; PRESTO, JST, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012 Japan
Junichi Yamamoto
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Satoshi Sakamoto
School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
Nobuhiro Nitta
National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan
Tomoko Asatsuma-Okumura
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Nobuyuki Shimizu
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Ryota Mizushima
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Ichio Aoki
National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan
Takeshi Imai
National Center for Geriatrics and Gerontology (NCGG), Aichi 474-8511, Japan
Yuki Yamaguchi
School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
Arnold J. Berk
Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles 90095, USA
Hiroshi Handa
Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan; Corresponding author
Summary: Thalidomide is a teratogen that causes multiple malformations in the developing baby through its interaction with cereblon (CRBN), a substrate receptor subunit of the CRL4 E3 ubiquitin ligase complex. CRBN was originally reported as a gene associated with autosomal recessive non-syndromic mild mental retardation. However, the function of CRBN during brain development remains largely unknown. Here we demonstrate that CRBN promotes brain development by facilitating the proliferation of neural stem cells (NSCs). Knockdown of CRBN in zebrafish embryos impaired brain development and led to small brains, as did treatment with thalidomide. By contrast, overexpression of CRBN resulted in enlarged brains, leading to the expansion of NSC regions and increased cell proliferation in the early brain field and an expanded expression of brain region-specific genes and neural and glial marker genes. These results demonstrate that CRBN functions in the determination of brain size by regulating the proliferation of NSCs during development. : Cellular Neuroscience; Developmental Neuroscience; Molecular Neuroscience Subject Areas: Cellular Neuroscience, Developmental Neuroscience, Molecular Neuroscience
