Combinatorial mechanisms specify cellular location and neurotransmitter identity during regeneration of planarian neurons.

During regenerative neurogenesis, neurons must be created in the right types and locations. Though regenerative neurogenesis is limited in humans, other animals use regenerative neurogenesis to faithfully restore form and function after brain injury. Planarians are flatworms with extraordinary capacity for brain regeneration. Planarians use pluripotent stem cells to create neurons after injury, rather than resident progenitors. In this context, genetic mechanisms that produce diverse neurons with correct local identity remain unknown. Here, we report the discovery of factors important for regenerative neurogenesis of dopaminergic neurons in the planarian central, peripheral, and pharyngeal nervous systems. Distinct genes promote dopaminergic neuronal identity and instruct neurons to inhabit regions of the nervous system. Our results demonstrate that planarian neuronal fate requires factors that simultaneously direct neurotransmitter choice and regional location. Our work suggests that combinatorial direction of cell type could inform and improve exogenous stem cell therapies aimed at precisely replacing neurons.