De novo truncations in
Interferon Regulatory Factor 2 Binding Protein Like
(
IRF2BPL
) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of
IRF2BPL
causes neural dysfunction, we examined its function in
Drosophila
and zebrafish. Overexpression of either
IRF2BPL
or
Pits
, the
Drosophila
ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased
wingless
(
wg
) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of
wg
in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of
irf2bpl
in zebrafish also causes neurological defects with an associated increase in
wnt1
transcription and downstream signaling.
WNT1
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.