Ontogenic cell death in the nigrostriatal system

Abstract

Like most neural systems, dopamine neurons of the substantia nigra undergo apoptotic natural cell death during development. In rodents, this occurs largely postnatally and is biphasic with an initial major peak just after birth and a second minor peak on postnatal day 14. As envisioned by classic neurotrophic theory, this event is regulated by interactions with the target of these neurons, the striatum, because a developmental target lesion results in an augmented natural cell death event with fewer nigral dopamine neurons surviving into adulthood. Until recently, the striatal target-derived neurotrophic factors providing developmental support of dopamine neurons were unknown, but there is now growing evidence that glial-cell-line-derived neurotrophic factor (GDNF) serves as a physiologic limiting neurotrophic factor for these neurons during the first phase of natural cell death. During this phase, intrastriatal injection of GDNF diminishes the natural cell death event and neutralizing antibodies augment it. Sustained overexpression of GDNF in the striatum throughout development in a unique double transgenic mouse model results in an increased number of dopamine neurons surviving the first phase of natural cell death. However, this increase does not persist into adulthood. Therefore, other factors or mechanisms must play important roles in the determination of the mature number of nigral dopamine neurons. Further elucidation of these mechanisms will be important in the development of neuroprotective and cell replacement therapies for Parkinson's disease.

RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice

“…Our extensive morphological, biochemical, and behavioral analysis demonstrate that RET deletion in both SNC and VTA dopaminergic neurons does not have deleterious effects on these cell types, as assessed by these parameters. Although our data demonstrate that Ret-mediated signaling does not affect the ultimate outcome (i.e., cell number) of the naturally occurring neural death (Burke, 2004), it is certainly possible that the timing of the events was altered in the conditional animals.…”

“…In animal models with markedly decreased or absent Ret signaling, it has been shown that Ret is not necessary for the embryonic development or the survival of the midbrain dopaminergic neurons perinatally (Airaksinen et al, 1999;Jain et al, 2004). The midbrain dopaminergic neurons undergo two rounds of apoptosis in the first 2-3 postnatal weeks before attaining their differentiated, defined role in the midbrain (Burke, 2004). Because neurodegenerative disorders such as PD are modeled in adult mice, we generated viable adult mice in which RET is specifically deleted in Ret-expressing dopaminergic neurons including the SNC and the VTA by using dopaminergic specific Cre (Cre expressed by Dat locus) (Zhuang et al, 2005).…”

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…Equally, GCs could influence the cascade of other factors, such as Nurr-1, that are known to induce and/or maintain the midbrain DA phenotype (Vitalis et al, 2005). Naturally occurring cell death via apoptotic mechanisms is also a process thought to play a critical role during late gestation and the neonatal period in regulating adult numbers of DA neurons in the SN (Jackson- Lewis et al, 2000;Oo et al, 2003;Burke, 2004;Kholodilov et al, 2004;Vitalis et al, 2005). Although GCs are often thought of as inducers of apoptosis (Schmidt et al, 2004), they can also suppress apoptosis and promote survival in certain cell types (Abraham et al, 2001;Amsterdam et al, 2002).…”

Novel CDNF/MANF family of neurotrophic factors

“…Cdnf and Manf are expressed in the developing nigro-striatal system of the mouse at P1 and P10 (Lindholm et al, 2007(Lindholm et al, , 2008, that is around the two postnatal PCD peaks of midbrain dopaminergic neurons at P2 and P14 (Burke, 2004), suggesting that CDNF and MANF may have a role in the development of midbrain dopaminergic system. In the adult mouse, MANF protein was also localized in THpositive dopaminergic neurons in the SN (Lindholm et al, 2008).…”