Inactivation of DET1 causes neurological defects and lethality in mice and humans I

COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Its transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here we show that a homozygous DET1R26W mutation that is linked to lethal developmental abnormalities in humans disrupts DET1 binding to DDB1 and compromises E3 ligase function. Human-induced pluripotent stem cells bearing the homozygous DET1R26W mutation expressed ETV4 and ETV5 highly, had alterations in mitochondrial protein expression, and exhibited impaired neuronal differentiation. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.