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Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson’s disease. The transcription factors  Otx2  and  Lmx1b  play a key role in the development of mdDA neurons. However, little is known about the genes downstream of  Otx2  and  Lmx1b  in the pathways controlling the formation of mdDA neurons  in vivo . Here we report on our investigation of  Lmx1b  as downstream target of  Otx2  in the formation of mdDA neurons. Mouse mutants expressing  Otx2  under the control of the  En1  promoter ( En1   +/Otx2 ) showed increased  Otx2  expression in the mid-hindbrain region, resulting in upregulation of  Lmx1b  and expansion of mdDA neurons there. In contrast,  Lmx1b    -/-   mice showed decreased expression of  Otx2  and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between  Otx2  and  Lmx1b , we generated compound mutants in which  Otx2  expression was restored in mice lacking  Lmx1b  ( En1   +/Otx2 ; Lmx1b    -/-  ). In these animals  Otx2  was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of  Lmx1b , but rescued the loss of ocular motor neurons. Gene expression studies in  Lmx1b    -/-   embryos indicated that in these mutants  Wnt1 ,  En1  and  Fgf8  expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that  Otx2  critically depends on  Lmx1b  for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that  Lmx1b  precisely maintains the expression pattern of  Wnt1 ,  Fgf8  and  En1 , which are essential for mid-hindbrain organizer function and the formation of mdDA neurons.

Otx2 Requires Lmx1b to Control the Development of Mesodiencephalic Dopaminergic Neurons