Clàudia Puigsasllosas Pastor

Understanding the development of midbrain dopaminergic (mesDA) neurons is essential for advancing cell replacement therapies for Parkinson’s disease. In the developing ventral midbrain (VM), radial glia (Rgl) cells are the progenitors of mesDA neurons. However, distinct Rgl subtypes have recently been identified, and their individual roles are unclear. Here we analyze transcriptomic data from mouse and human VM Rgl to define their contributions to mesDA neuron development. We identify Rgl1 as the progenitor of the mesDA lineage, and reveal a Rgl1 transcriptional network coordinated by BMAL1 , which we validate as a new regulator of mesDA neurogenesis. Moreover, we uncover Rgl3 as a key signaling subtype and show that factors expressed by Rgl3 promote the survival and yield of human stem cell-derived mesDA neurons. Our findings delineate distinct roles of Rgl subtypes, elucidate lineage relationships in the developing VM and uncover new factors that improve the derivation of clinically relevant human mesDA neurons.

Cell therapy has proven to be a promising treatment for a range of neurological disorders, including Parkinson Disease, drug-resistant epilepsy, and stroke, by restoring function after brain damage. Nevertheless, evaluating the true effectiveness of these therapeutic interventions requires a deep understanding of the functional integration of grafted cells into existing neural networks. This review explores a powerful arsenal of molecular techniques revolutionizing our ability to unveil functional integration of grafted cells within the host brain. From precise manipulation of neuronal activity to pinpoint the functional contribution of transplanted cells by using opto- and chemo-genetics, to real-time monitoring of neuronal dynamics shedding light on functional connectivity within the reconstructed circuits by using genetically encoded (calcium) indicators in vivo. Finally, structural reconstruction and mapping communication pathways between grafted and host neurons can be achieved by monosynaptic tracing with viral vectors. The cutting-edge toolbox presented here holds immense promise for elucidating the impact of cell therapy on neural circuitry and guiding the development of more effective treatments for neurological disorders.