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

doi:10.1016/j.isci.2019.04.007

Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation

iScience. 2019 May 31:15:95-108. doi: 10.1016/j.isci.2019.04.007. Epub 2019 Apr 9.

Authors

Affiliations

¹ Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
² 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.
³ School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
⁴ National Institute of Radiological Sciences (NIRS), Chiba 263-8555, Japan.
⁵ National Center for Geriatrics and Gerontology (NCGG), Aichi 474-8511, Japan.
⁶ Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles 90095, USA.
⁷ Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address: hhanda@tokyo-med.ac.jp.

Abstract

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.

Keywords: Cellular Neuroscience; Developmental Neuroscience; Molecular Neuroscience.