Frank M. J. Jacobs, Annemarie J. A. van der Linden, Yuhui Wang, Lars von Oerthel, Hei Sook Sul, J. Peter H. Burbach, and Marten P. Smidt
The orphan nuclear receptor Nurr1 is essential for the development of
meso-diencephalic dopamine (mdDA) neurons and is required, together with the
homeobox transcription factor Pitx3, for the expression of genes involved in
dopamine metabolism. In order to elucidate the molecular mechanisms that
underlie the neuronal deficits in Nurr1-/- mice, we
performed combined gene expression microarrays and ChIP-on-chip analysis and
thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1
target genes in vivo. In line with the previously described cooperativity
between Nurr1 and Pitx3, we show that the expression of Ptpru and
Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, we
demonstrate that Nurr1 interacts with the Ptpru promoter directly and
requires Pitx3 for full expression of Ptpru in mdDA neurons. By
contrast, the expression of Dlk1 is maintained in
Pitx3-/- embryos and is even expanded into the rostral
part of the mdDA area, suggesting a unique position of Dlk1 in the
Nurr1 and Pitx3 transcriptional cascades. Expression analysis in
Dlk1-/- embryos reveals that Dlk1... |