Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila

Nat Commun. 2025 Nov 26;16(1):11651. doi: 10.1038/s41467-025-66727-3.

ABSTRACT

The ability of neural stem cells (NSCs) to switch between quiescent and proliferative states is fundamental for adult neurogenesis and regeneration. Microproteins or short open reading frame (sORF)-encoded peptides (SEPs), are highly abundant yet largely understudied, and their role in brain development remains unclear. Here, we demonstrate that two evolutionarily-conserved microprotein paralogs, Simba1 and Simba2, encoded by sORFs CG15715 and CG18081, respectively, govern the reactivation of Drosophila quiescent NSCs. Both Simba1 and Simba2 function in NSCs and Blood-Brain-Barrier (BBB) glial cells to promote NSC reactivation. Mechanistically, Simba1 and Simba2 act as transcription factors activating the WNT/Wingless signalling pathway during NSC reactivation. We uncover a critical role of Wg signalling molecules in promoting NSC reactivation and the translocation of Wingless from BBB glia to NSCs. Our findings reveal a role for microproteins Simba1/2 in regulating NSC reactivation through Wg signalling. Moreover, our bioinformatic analysis and luciferase assay suggest that ZNF706, the human ortholog of Simba1/2, is required for WNT signaling activation in human cells. The conserved function of Simba1/2/ZNF706 in activating WNT/Wg signalling in Drosophila and humans suggests that this new regulatory paradigm may be applicable to broader cellular processes and disease conditions.

PMID:41298547 | PMC:PMC12749969 | DOI:10.1038/s41467-025-66727-3