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Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila
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Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila
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Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila
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Journal Article
Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila
2025
Overview
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.
Drosophila
Microproteins Simba1/2 act in neural stem cells and blood-brain-barrier glia to promote reactivation of neural stem cells via activating WNT/Wingless signaling, while human ortholog ZNF706 is found to have a conserved role in activating WNT pathway.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/15
/ 38/77
/ 38/89
/ 45/22
/ 45/23
/ 64/24
/ 82/1
/ 82/51
/ 96
/ Animals
/ Blood
/ Brain
/ Coding
/ CRISPR
/ Drosophila melanogaster - genetics
/ Drosophila melanogaster - metabolism
/ Drosophila Proteins - genetics
/ Drosophila Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Insects
/ Insulin
/ Kinases
/ Mutation
/ Neural Stem Cells - cytology
/ Neural Stem Cells - metabolism
/ Peptides
/ Proteins
/ Roles
/ Science
/ Transcription Factors - genetics
