Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation

Exp Neurol. 2007 Apr;204(2):791-801. doi: 10.1016/j.expneurol.2007.01.014. Epub 2007 Jan 24.


Affymetrix GeneChip technology and quantitative real-time PCR (Q-PCR) were used to examine changes in gene expression in the adult murine substantia nigra pars compacta (SNc) following lentiviral glial cell line-derived neurotrophic factor (GDNF) delivery in adult striatum. We identified several genes that were upregulated after GDNF treatment. Among these, the gene encoding the transmembrane protein Delta-like 1 homologue (Dlk1) was upregulated with a greater than 4-fold increase in mRNA encoding this protein. Immunohistochemistry with a Dlk1-specific antibody confirmed the observed upregulation with increased positive staining of cell bodies in the SNc and fibers in the striatum. Analysis of the developmental regulation of Dlk1 in the murine ventral midbrain showed that the upregulation of Dlk1 mRNA correlated with the generation of tyrosine hydroxylase (TH)-positive neurons. Furthermore, Dlk1 expression was analyzed in MesC2.10 cells, which are derived from embryonic human mesencephalon and capable of undergoing differentiation into dopaminergic neurons. We detected upregulation of Dlk1 mRNA and protein under conditions where MesC2.10 cells differentiate into a dopaminergic phenotype (41.7+/-7.1% Dlk1+ cells). In contrast, control cultures subjected to default differentiation into non-dopaminergic neurons only expressed very few (3.7+/-1.3%) Dlk1-immunopositive cells. The expression of Dlk1 in MesC2.10 cells was specifically upregulated by the addition of GDNF. Thus, our data suggest that Dlk1 expression precedes the appearance of TH in mesencephalic cells and that levels of Dlk1 are regulated by GDNF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line, Transformed
  • Dopamine / metabolism*
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Humans
  • Indoles
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lentivirus / physiology
  • Membrane Proteins / metabolism*
  • Mice
  • Oligonucleotide Array Sequence Analysis / methods
  • Substantia Nigra / metabolism*
  • Substantia Nigra / virology


  • Dll3 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • DAPI
  • Dopamine