Mex3a as a post-transcriptional regulator of neurogenesis in the adult brain

Resumen

Tissue-resident adult stem cells (SCs) constitute a unique pool of undifferentiated cells responsible for tissue maintenance and potential regeneration after injury. All somatic SCs are defined by their ability to produce differentiated progeny (developmental potential) while preserving the capacity to self-replicate (self-renewal). In many adult tissues, SCs co-exist in several states of activation, being the quiescent reversible cell cycle-arrested state responsible for the long-term maintenance of the SC pool. Cell state transitions in these populations, such as activation and differentiation, must be tightly regulated to maintain homeostatic balance. Such state changes are dynamic and rely on the action of post-transcriptional and translational mechanisms over pre-existing transcripts, ensuring that proteomes can be rapidly adapted to the new state in a precise and coordinated manner before a different transcription program comes into effect. SCs from different tissues show the lowest rates of mRNA translation among their lineage. Cell fate decisions the most affected by small imbalances in protein synthesis, suggesting that simultaneous transcription of genes that encode proteins with conflicting functions (i.e., self-renew or differentiate) entails a critical challenge for state transition. SCs can address this problem by fine-tuning protein production to achieve timely commitment using target-specific mechanisms, which frequently involve trans-acting factors such as RNA-binding proteins (RBPs). Much effort has been invested in learning how proteostasis is regulated and its role on stemness in the last decade, yet many questions remain unanswered. Recent studies have uncovered that transcription-translation uncoupling plays an important role at specific cell transitions along the subependymal neurogenic lineage, but potential regulators remain largely unexplored. This work assesses the role of the evolutionary conserved RBP MEX3A in adult murine neurogenesis and unveils the transcriptional programs post-transcriptionally regulated by this RBP in the subependymal zone (SEZ) niche. Our results reveal that MEX3A is restricted to areas of the adult brain where new neuroblasts are generated and demonstrate an essential role for MEX3A in the maintenance of the neural stem cell (NSC) population in the neurogenic/oligodendrogenic SEZ niche over time and in the timely differentiation of the subependymal neuronal lineage. The results also provide novel insights into the molecular signatures associated to NSC quiescence and priming as well as to cell cycle exit at the onset of differentiation.