Wnt signaling plays a pivotal role in normal brain development and function. Dickkopf-related protein 2 (DKK2), a member of the DKK protein family (DKK1 - 4), modulates Wnt signaling either positively or negatively by interacting with the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5/6). However, the role of DKK2 in the brain remains unclear. Here, we demonstrated that the DKK2-mediated suppression of Wnt signaling is essential for hippocampal function. Dkk2+/- mice exhibited impaired context discrimination and reduced adult hippocampal neurogenesis (AHN). Genetic disruption of Dkk2 (Dkk2+/- and Dkk2-/-) and chronic DKK2 administration into the brain affected AHN bidirectionally. Furthermore, homozygous and heterozygous Dkk2 deletions exerted differential effects on the Wnt signaling pathway in the hippocampus. Complete loss of Dkk2 enhanced both Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling, whereas haploinsufficiency primarily enhanced Wnt/PCP signaling. In hippocampal slices, DKK2 suppressed Wnt3a- and Wnt5a-mediated activation of Wnt/β-catenin and Wnt/PCP signaling, respectively. Chronic suppression of c-Jun N-terminal kinase (JNK) signaling rescued the impaired AHN and context discrimination in Dkk2+/- mice. Collectively, these findings identify DKK2 as a negative regulator of Wnt signaling that paradoxically promotes AHN and suggest that suppressing Wnt/PCP signaling may enhance AHN.
© 2025. The Author(s).