Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons.
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 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathology as observed in Parkinson's disease.
Jacobs
Frank M J
FM
Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
van der Linden
Annemarie J A
AJ
Wang
Yuhui
Y
von Oerthel
Lars
L
Sul
Hei Sook
HS
Burbach
J Peter H
JP
Smidt
Marten P
MP
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004027:Diencephalon / Q000166:cytology* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C512925:Dlk1 protein, mouse; D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C514889:KLHL1 protein, mouse; D008840:Microfilament Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C493215:Slc6a3 protein, mouse; D014157:Transcription Factors; C433629:homeobox protein PITX3; C516869:Ptpru protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D004298:Dopamine