The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons

Chee Yeun Chung, Pawel Licznerski, Kambiz N. Alavian, Antonio Simeone, Zhicheng Lin, Eden R Martin, Jeffery M Vance, Ole Isacson

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson's disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease. Here, we demonstrate elevated expression of the transcription factor orthodenticle homeobox 2 in A10 dopaminergic neurons of embryonic and adult mouse, primate and human midbrain. Overexpression of orthodenticle homeobox 2 using lentivirus increased levels of known A10 elevated genes, including neuropilin 1, neuropilin 2, slit2 and adenylyl cyclase-activating peptide in both MN9D cells and ventral mesencephalic cultures, whereas knockdown of endogenous orthodenticle homeobox 2 levels via short hairpin RNA reduced expression of these genes in ventral mesencephalic cultures. Lack of orthodenticle homeobox 2 in the ventral mesencephalon of orthodenticle homeobox 2 conditional knockout mice caused a reduction of midbrain dopaminergic neurons and selective loss of A10 dopaminergic projections. Orthodenticle homeobox 2 overexpression protected dopaminergic neurons in ventral mesencephalic cultures from Parkinson's disease-relevant toxin, 1-methyl-4-phenylpyridinium, whereas downregulation of orthodenticle homeobox 2 using short hairpin RNA increased their susceptibility. These results show that orthodenticle homeobox 2 is important for establishing subgroup phenotypes of post-mitotic midbrain dopaminergic neurons and may alter neuronal vulnerability.

Original languageEnglish
Pages (from-to)2022-2031
Number of pages10
JournalBrain
Volume133
Issue number7
DOIs
StatePublished - Jul 1 2010

Fingerprint

Homeobox Genes
Dopaminergic Neurons
Mesencephalon
Transcription Factors
antineoplaston A10
Small Interfering RNA
Parkinson Disease
Neuropilin-2
Neuropilin-1
1-Methyl-4-phenylpyridinium
Phenotype
Lentivirus
Ventral Tegmental Area
Adenylyl Cyclases
Knockout Mice
Primates
Down-Regulation
Gene Expression
Peptides

Keywords

  • axon
  • neuropeptides
  • Parkinson's disease
  • protection
  • transcription factor

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons. / Chung, Chee Yeun; Licznerski, Pawel; Alavian, Kambiz N.; Simeone, Antonio; Lin, Zhicheng; Martin, Eden R; Vance, Jeffery M; Isacson, Ole.

In: Brain, Vol. 133, No. 7, 01.07.2010, p. 2022-2031.

Research output: Contribution to journalArticle

Chung, Chee Yeun ; Licznerski, Pawel ; Alavian, Kambiz N. ; Simeone, Antonio ; Lin, Zhicheng ; Martin, Eden R ; Vance, Jeffery M ; Isacson, Ole. / The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons. In: Brain. 2010 ; Vol. 133, No. 7. pp. 2022-2031.
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