Specification and Survival of Dopaminergic Neurons in the Mammalian Midbrain

Abstract

Dopaminergic (DA) neurons in the mammalian midbrain play a seminal role in postural reflex, reward-associated behavior, and learning, and their loss or abnormal function has been linked to Parkinson's disease, schizophrenia, and drug addiction. It has been shown that several members of the transforming growth factors (TGF) TGF β protein family including, in addition to glial-cell line-derived neurotrophic factor (GDNF), TGF β 2 and - β 3 can prevent the death of cultured rat embryonic midbrain DA neurons at picomolar concentrations. It is found that TGF β 2 and - β 3 and GDNF are expressed sequentially as local and target-derived trophic factors and that subpopulations of DA neurons projecting to the striatum would have access to GDNF whereas DA neurons projecting to the cortical and limbic system would have access mainly to the TGFs. GDNF appears to be the most potent and efficacious survival factor for DA neurons known so far. In addition, it has been found that GDNF is a potent survival factor for distinct populations of sensory and sutonomic nervous system neurons. The discrepancy between the efficacy of GDNF as a survival factor for multiple neuronal populations in culture and the mild neuronal deficient observed in GDNF-deficient mice suggested that in vivo GDNF-like proteins may compensate for its absence. In addition, it is showed that transgenic mice that harbor a supernumerary floor plate in the dorsal midbrain region develop a duplicated cluster of DA adjacent to the ectopic floor plate. The types of cell that developed in this midbrain explant appeared to be dependent on the concentration of sonic hedgehog (SHH). Thus, the genesis and survival of DA neurons are complex processes regulated by multiple growth factors that utilize diverse signaling systems.