Depletion of Polypyrimidine tract binding protein 1 (ptbp1) activates Müller glia-derived proliferation during zebrafish retina regeneration via modulation of the senescence secretome

Polypyrimidine Tract Binding protein 1 (PTB) is an alternative splicing factor linked to neuronal induction and maturation. Previously, knockdown experiments supported a model in which PTB can function as a potent reprogramming factor, able to elicit direct glia-to-neuron conversion in vivo, in both the brain and retina. However, later lineage tracing and genetic knockouts of PTB did not support direct neuronal reprogramming. Nevertheless, consistent with the PTB depletion experiments, we show that antisense knockdown of PTB (ptbp1a) in the zebrafish retina can activate Müller glia-derived proliferation and that depletion of PTB can further enhance proliferation when combined with acute NMDA damage. The effects of PTB are consistent with a role in controlling key senescence and pro-inflammatory genes that are part of the senescence secretome that initiates retina regeneration.