Pitx3 is Necessary for Survival of Midbrain Dopaminergic Neuron Subsets Relevant to Parkinson’s Disease

Abstract

The pathological hallmark of Parkinson’s disease (PD) is progressive loss of midbrain dopaminergic (DA) neurons, accompanied by loss of non-DA populations in more advanced stages (Hassler, 1938; Jellinger, 2001). Midbrain DA neurons are localized in the densely packed substantia nigra (SN) pars compacta, and more loosely packed cells intermingled with GABAergic neurons in the SN pars reticulata, the SN pars lateralis, the ventral tegmental area (VTA) and the retrorubral field (Parent, 1996). The RRF, SN, VTA, are also designated as catecholaminergic areas A8, A9, and 10, respectively (Hokfelt et al., 1984). Three tiers of DA cells are identified in the rodent and primate SN: a dorsal tier of the SN pars compacta (SNc), and the two ventral tiers; one within the SNc proper with the other occupying the SN pars reticulata (SNr). The SN dorsal tier may be distinguished from the ventral tiers by cytological criteria, and expression of the calcium binding proteins calbindin-D-28k (CB) and/or calretinin (CR) in rodents, non-human primates and humans (Cote et al., 1991; Liang et al., 1996; McRitchie et al., 1996). The pattern of progressive midbrain DA (mDA) neuronal loss in PD is not uniform: mDA subpopulations differ in vulnerability to injury. For example, in the SN, DA neurons that occupy the ventral two tiers (“ventral SN”) are lost first, with relative sparing of the DA neurons in the dorsal tier and VTA. While CB expression was initially thought to confer resistance to toxicity (Yamada et al., 1990; Lavoie and Parent, 1991), knockout of CB in transgenic mice does not alter developmental survival of mDA neurons nor enhance