Combinatorial mechanisms specify cellular location and neurotransmitter identity during planarian neurogenesis

Regenerative neurogenesis can drive replacement of neurons in the right types and locations to faithfully restore form and function after injury. The genetic mechanisms underlying successful regenerative neurogenesis, including mechanisms that produce neuronal diversity and spatial organization, remain poorly understood. Planarians are flatworms with extraordinary capacity for brain regeneration made possible by pluripotent stem cells throughout the body that undergo neurogenesis to form a complex nervous system anew after injury. Here, we focus on the dopaminergic neuron identity and report the discovery of factors important for regenerative neurogenesis of this neuron type in the planarian central, peripheral, and pharyngeal nervous systems. Distinct genes, including irx4/6, fli1-2, soxB1-2, foxA, app-L1, and lmo1/3-1, promote dopaminergic neuronal regeneration and maintenance in distinct parts of the nervous system. Our results demonstrate that planarian neurogenesis requires coordination of factors that initiate neurotransmitter choice and regional location. Our work suggests that combinatorial instruction of cell type and spatial identity could improve exogenous stem cell therapies aimed at precisely replacing neurons after localized injuries. During regeneration, new neurons need to be made in a way that reproduces both neuronal diversity and organization. Here the authors show that a combination of factors works cooperatively to direct neuron type and place in brain regeneration in planarians.