Related Experiment Video
Updated: Jan 10, 2026
Neural Stem Cell Reactivation in Cultured Drosophila Brain Explants
Published on: May 18, 2022
Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in
Jiaen Lin1, Qiannan Deng1,2, Yang Gao1
1Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, 8 College Road, Singapore, Singapore.
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.
Insights
Two microproteins, Simba1 and Simba2, regulate neural stem cell (NSC) reactivation by activating WNT/Wingless signaling. This finding reveals a conserved mechanism for brain regeneration and development in both flies and humans.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Neural stem cell (NSC) quiescence and proliferation are crucial for adult neurogenesis and regeneration.
- Microproteins (or short open reading frame-encoded peptides, SEPs) are abundant but their roles in brain development are largely unknown.
Purpose of the Study:
- To investigate the function of microproteins in regulating quiescent neural stem cell reactivation.
- To elucidate the molecular mechanisms underlying microprotein-mediated NSC reactivation.
Main Methods:
- Genetic analysis in Drosophila melanogaster.
- Investigation of microprotein function in NSCs and Blood-Brain-Barrier (BBB) glial cells.
- Analysis of WNT/Wingless signaling pathway activation.
- Bioinformatic analysis and luciferase assays in human cells.
Main Results:
- Two microproteins, Simba1 and Simba2, were identified as regulators of quiescent NSC reactivation in Drosophila.
- Simba1 and Simba2 function in both NSCs and BBB glial cells to promote NSC reactivation.
- Simba1 and Simba2 act as transcription factors that activate the WNT/Wingless signaling pathway, facilitating Wingless translocation from BBB glia to NSCs.
- The human ortholog of Simba1/2, ZNF706, is suggested to be involved in WNT signaling activation in human cells.
Conclusions:
- Microproteins Simba1 and Simba2 play a critical role in regulating neural stem cell reactivation through the WNT/Wingless signaling pathway.
- The conserved function of Simba1/2 and its human ortholog ZNF706 in WNT/Wg signaling activation suggests a novel regulatory paradigm applicable to broader biological processes and diseases.
