Shared proteomic and transcriptomic signatures of molecularly-induced feedback and feedforward wiring of adult hippocampal neurons

Molecular programming by basic helix-loop-helix (bHLH) proteins can potently reactivate axon growth in adult neurons, enabling the investigation of the mechanisms and the potentials of adult brain rewiring. Here, we focused on the mechanisms by studying proteomic and transcriptomic changes during Id2- (a bHLH transcriptional regulator) and Ascl4- (a bHLH transcription factor) induced feedback and feedforward wiring of adult hippocampal granule cells. Despite these differences, we find that Id2 and Ascl4 share a molecular cascade through the transcription factor Stat1 and co-regulate a set of proteins, which potentially constitute a core program for adult wiring. Unexpectedly, we also identify shared molecular changes which do not directly originate from the reprogrammed neurons, but from endothelial cells and microglia. Together, our results indicate that adult brain wiring is regulated by specific molecular programs and dynamic interactions between the wiring neurons and the circuit environment.