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

Abstract

Thalidomide is a teratogen that causes multiple malformations when exposed to developing vertebrate embryos. This was recently shown to be due to its interaction with Cereblon (CRBN), a novel substrate receptor subunit of the CRL4 E3 ubiquitin ligase complex, whose enzymatic activity is controlled by thalidomide and its analogs. 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 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 in the telencephalon, the diencephalon and the midbrain, increased cell proliferation throughout the brain, and an expanded expression of brain region-specific genes and neural and glial marker genes. CRBN functions downstream of Six3 and Lhx2 to regulate neural stem cell proliferation. These results demonstrate a new function for CRBN in the determination of brain size by regulating proliferation of NSCs during development.