Ubiquitin ligase COP1 coordinates transcriptional programs that control cell type specification in the developing mouse brain.

The E3 ubiquitin ligase CRL4 ^COP1/DET1 is active in the absence of ERK signaling, modifying the transcription factors ETV1, ETV4, ETV5, and c-JUN with polyubiquitin that targets them for proteasomal degradation. Here we show that this posttranslational regulatory mechanism is active in neurons, with ETV5 and c-JUN accumulating within minutes of ERK activation. Mice with constitutive photomorphogenesis 1 ( Cop1 ) deleted in neural stem cells showed abnormally elevated expression of ETV1, ETV4, ETV5, and c-JUN in the developing brain and spinal cord. Expression of c-JUN target genes Vimentin and Gfap was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including Olig1 , Olig2 , and Sox10. The mice had subtle morphological abnormalities in the cerebral cortex, hippocampus, and cerebellum by embryonic day 18 and died soon after birth. Elevated c-JUN, ETV5, and ETV1 contributed to the perinatal lethality, as several Cop1 -deficient mice also lacking c-Jun and Etv5 , or lacking Etv5 and heterozygous for Etv1 , were viable.
Competing Interests: Conflict of interest statement: All authors were employees of Genentech.
(Copyright © 2018 the Author(s). Published by PNAS.)