Clinical interest has focused on the midbrain dopaminergic neurons due to their involvement in many neurological and psychiatric diseases. Considerable progress has been made on the biology and development of these neurons in an effort to understand how to treat such devastating illnesses. For example, many transcription factors that determine midbrain dopaminergic neuron phenotype have been identified, including nuclear receptor related 1 protein, pituitary homeobox 3, LIM homeobox transcription factors 1a and 1b, homeobox protein engrailed-1 (En1) and orthodenticle homeobox 2 (Otx2) (Ang, 2006
; Prakash and Wurst, 2006
). Even within midbrain dopaminergic neurons, there are two major subgroups; A9 dopaminergic neurons in the substantia nigra (SN) and A10 dopaminergic neurons in the ventral tegmental area (VTA). In addition to their anatomical location in the midbrain, their axons project to distinct targets; A9 dopaminergic neurons to the dorsolateral striatum and A10 dopaminergic neurons to the nucleus accumbens, cortex, septum, amygdala and olfactory tubercle. Moreover, these neurons show different susceptibility in Parkinson’s disease. Independent of specific aetiology, A9 dopaminergic neurons in the SN preferentially degenerate, whereas A10 dopaminergic neurons in the adjacent VTA are relatively spared. Our previous study demonstrated that molecular differences between A9 and A10 dopaminergic neurons may explain some aspects of their differential vulnerability (Chung et al., 2005
). Understanding the transcriptional control determining these distinct dopaminergic neuronal populations will be a critical advance in developing therapies for the diseases caused by the dysfunction of these neurons.
Little is known about transcription factors that control the distinct phenotypes of midbrain dopaminergic neurons. Our previous laser capture microdissection (LCM) and microrray study in mice brought to light a well-known transcription factor, Otx2, as a potential contributor to subgroup specification of midbrain dopaminergic neurons since Otx2 messenger RNA levels were highly elevated in adult A10 dopaminergic neurons by approximately 6-fold compared with adult A9 dopaminergic neurons (Chung et al., 2005
). Otx2 is a homeodomain transcription factor, whose expression is restricted to the forebrain and midbrain in the nervous system during development (Ang, 2006
; Prakash and Wurst, 2006
). Otx2 plays an important role in the proliferation and differentiation of midbrain dopaminergic neuronal progenitors during mitosis, demonstrated by studies using various Otx2 mutant mice (Puelles et al., 2004
; Vernay et al., 2005
; Omodei et al., 2008
). In adult mice, elimination of Otx2 expression in the basal midbrain region overlapping the En1 expression domain resulted in a selective loss of axonal projection from dopaminergic neurons in the VTA, despite of an equal reduction in the number of midbrain dopaminergic neurons from both SN and VTA (Borgkvist et al., 2006
). In light of these findings, we demonstrate that Otx2 is elevated in post-mitotic A10 dopaminergic neurons in mice and humans, and the levels of Otx2 affect the pattern of A10 axonal projection and vulnerability of midbrain dopaminergic neurons to a Parkinson’s disease-relevant toxin. These results suggest that differential expression of Otx2 between A9 and A10 dopaminergic neurons may be one of many ways to establish subgroup phenotypes of post-mitotic midbrain dopaminergic neurons.