Dopaminergic neurons in the ventral midbrain (VM), also known as mesencephalic dopaminergic (mesDA) neurons, control voluntary movements, and their degeneration is associated with Parkinson's disease (PD). In the course of brain development, the establishment of correct VM progenitor domain identity depends on the transcription factor Otx2, but is Otx2 important for mesDA neurogenesis? The answer, as Daniela Omodei and co-workers report on , is yes. By analysing mouse mutants that conditionally overexpress Otx2 in the mesencephalon, the authors reveal that too much Otx2 leads to selectively increased mesDA progenitor proliferation and to the expansion of the mesDA progenitor domain. This occurs in a dosage-dependent and anteroposteriorly graded manner. Conversely, lack of Otx2 dramatically reduces mesDA progenitor proliferation and causes early cell cycle exit. The authors also show that Otx2 controls mesDA progenitor proliferation via the canonical Wnt pathway and promotes progenitor differentiation by inducing an intricate transcription factor cascade. These findings flag Otx2 as a potential target for future cell-replacement therapies for PD.
