title: The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons.
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.
authors.affiliation: Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.forename: Pawel
authors.initials: P
authors.lastname: Licznerski
authors.forename: Kambiz N
authors.initials: KN
authors.lastname: Alavian
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
authors.forename: Eden
authors.initials: E
authors.lastname: Martin
authors.forename: Jeffery
authors.initials: J
authors.lastname: Vance
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051857:Otx Transcription Factors / Q000502:physiology*; D010641:Phenotype
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine