Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling.

De novo truncations in () lead to severe childhood-onset neurodegenerative disorders. To determine how loss of causes neural dysfunction, we examined its function in and zebrafish. Overexpression of either or , the ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased () levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of in zebrafish also causes neurological defects with an associated increase in transcription and downstream signaling. is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling.