Molecular mechanisms of dopaminergic subset specification: fundamental aspects and clinical perspectives

Dopaminergic (DA) neurons in the ventral mesodiencephalon control locomotion and emotion and are affected in psychiatric and neurodegenerative diseases, such as Parkinson's disease (PD). A clinical hallmark of PD is the specific degeneration of DA neurons located within the substantia nigra (SNc), whereas neurons in the ventral tegmental area remain unaffected. Recent advances have highlighted that the selective vulnerability of the SNc may originate in subset-specific molecular programming during DA neuron development, and significantly increased our understanding of the molecular code that drives specific SNc development. We here present an up-to-date overview of molecular mechanisms that direct DA subset specification, integrating our current knowledge about subset-specific roles of transcription factors, signaling pathways and morphogenes. We discuss strategies to further unravel subset-specific gene-regulatory networks, and the clinical promise of fundamental knowledge about subset specification of DA neurons, with regards to cell replacement therapy and cell-type-specific vulnerability in PD.