Influences Correct Post-mitotic Coding of Mesodiencephalic Dopaminergic Neurons.

The Lim Homeobox transcription factor 1 beta (LMX1b) has been identified as one of the transcription factors important for the development of mesodiencephalic dopaminergic (mdDA) neurons. During early development, is essential for induction and maintenance of the Isthmic Organizer (IsO), and genetic ablation results in the disruption of inductive activity from the IsO and loss of properly differentiated mdDA neurons. To study the downstream targets of Lmx1b without affecting the IsO, we generated a conditional model in which was selectively deleted in -expressing cells from embryonic day (E)13 onward. Supporting previous data, no significant changes could be observed in general dopamine (DA) marks, like at E14.5. However, in depth analysis by means of RNA-sequencing revealed that is important for the mRNA expression level of survival factors and and for the repression of mdDA subset mark during (late) development. Interestingly, the regulation of by was found to be independent, since mRNA levels were not altered in conditional knock-outs (cKOs) and expression was also up-regulated in double mutants compared to mutants. Further analysis of cKOs showed that post-mitotic deletion of additional leads to a loss of TH+ cells at 3 months age both in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Remarkably, different cell types were affected in the SNc and the VTA. While TH+AHD2+ cells were lost the SNc, TH+AHD2- neurons were affected in the VTA, reflected by a loss of expression, indicating that is important for the survival of a sub-group of mdDA neurons.