Ring1b control of fate specification and re-specification in adult-born neurons

Despite the promise of direct neuronal reprogramming to drive transformative research, several challenges hinder its practical application in multiple contexts. Among them, the mechanisms safeguarding cellular identities in adult neurons may obstruct conversion between neuronal lineages and hinder the generation of specific induce neuron (iN) subtypes from non-neuronal cells. This study investigates whether the epigenetic regulator Ring1b, a crucial component of the Polycomb-Repressive-Complex-1 that controls neuronal specification in development, plays a role in the mentioned mechanisms. We first generated a floxed-mouse model that selective deplete Ring1b in adult neural stem cells and used it to explore whether this gene regulates neuronal specification during adult neurogenesis. Upon Ring1b depletion, adult-born neurons at the olfactory bulb (OB) and dentate gyrus display morphological anomalies, aberrant migration patterns, mislocalization, and/or atypical expression and transcriptional signatures, suggestive of altered neuronal specification. Supporting this notion, we observed that upon Ring1b depletion, certain neuronal subsets such as OB secretagogin+ and dopaminergic neurons were reduced or absent. Next, we tested whether Ring1b is involved in the persistence of neuronal subtype lineages in adult-born neurons, thereby blocking reprogramming between neuronal subtypes in this context. To this goal, we targeted the murine adult rostral migratory stream through injection of a retrovirus encoding the glutamatergic determinant Neurog2, and found that upon Ring1b-depletion, Neurog2-expressing neuroblasts differentiate into Tbr2 and Tbr1 expressing glutamatergic neurons. Overall, our results identify Ring1b as a crucial factor in specifying adult-born neurons and spotlight its expression manipulation as a promising strategy for neuron-to-neuron reprogramming and iN subtype differentiation.