Conditional knockout mouse model demonstrates that Copa expression is required for viability in development and adulthood.

The COPI coatomer is a heptameric complex that regulates traffic between the Golgi apparatus and the Endoplasmic Reticulum (ER). Mutations in the COPA gene encoding the alpha subunit of the COPI complex result in an autoimmune disorder impacting multiple tissues including the lungs, joints, and kidneys. We report here the characterization of a conditional-ready Copa knockout mouse. Systemic homozygous deletion of Copa in mice resulted in embryonic lethality. Deletion of Copa in Chat-positive cells also resulted in late embryonic lethality. However, the deletion of Copa by Cre recombinase expression under the Mnx1 promoter was compatible with development and viability. In adulthood, these mice display a modest glucose intolerance, most likely due to Mnx1-driven pancreatic expression of Cre recombinase. Systemic deletion of Copa in adult mice results in rapid decline and death. Lung fibroblasts cultured from mice expressing a Tamoxifen-inducible Cre recombinase demonstrate robust Copa knockout, resulting in near complete loss of alpha-COP protein. These cultures recapitulate the previously described COPA syndrome phenotype, including hyperactivation of STING (Stimulator of Interferon Genes) signaling and induction of ER stress. Dorsal Root Ganglion neurons cultured from Tamoxifen-inducible Copa knockout mice show that axonal arbor maintenance and viability requires Copa expression.