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

Abstract

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 <i>constitutive photomorphogenesis 1</i> (<i>Cop1</i>) 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 <i>Vimentin</i> and <i>Gfap</i> was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including <i>Olig1</i>, <i>Olig2</i>, and <i>Sox10.</i> 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 <i>Cop1</i>-deficient mice also lacking <i>c-Jun</i> and <i>Etv5</i>, or lacking <i>Etv5</i> and heterozygous for <i>Etv1</i>, were viable.