Dopaminergic Differentiation Potential of Neural Precursor Cells Derived from Embryonic Stem Cells

Abstract

One major question in mammalian development is how the diverse cell types of the adult organism are generated from the initial population of undifferentiated cells in the preimplantation embryo. As part of this diversification process, the variety of neurons of the adult brain is generated from neural precursors specified during gastrulation and the posterior neurulation phase. The specification of neural precursors has a definitive influence on the fate of these cells and, consequently, in the neuron type derived after differentiation. Embryonic stem cells (ESCs), pluripotent cells derived from the inner cell mass of the blastocyt, can be used as a source of different neuron types in vitro, and the process of neuronal differentiation can thus be studied from the earliest stages starting from naive non-neural undifferentiated cells. In particular, differentiation of ESCs into dopaminergic neurons has attracted a lot of attention for the relevance it may have in the design of cellular treatments for Parkinson’s illness, a neurodegenerative disease characterized by the specific death of these neurons. The midbrain dopaminergic (mDA) neurons constitute about 75% of all dopaminergic neurons in the adult brain(Wallen & Perlmann, 2003). They are located in the ventral region of the mesencephalon where they are organized laterally in the retrorubral field (RRF) and the substantia nigra pars compacta (SNc), and medially in the ventral tegmental area (VTA). The SNc neurons project to the dorsal striatum, forming the nigrostriatal pathway involved in the control of voluntary movements, and degeneration of this group of mDA neurons provokes the characteristic symptoms of Parkinson’s disease (von Bohlen und Halbach, 2004). The neurons of the VTA project to the ventromedial striatum and the subcortical and cortical areas, forming the mesocortical limbic system, which is involved in emotional behaviors and mechanisms of motivation and reward. Misregulation of mesocortical limbic system has been involved in the development of drug addiction and depression (Kelley & Berridge, 2002), and contributes to certain symptoms of schizophrenia (Egan & Weinberger, 1997). Unlike SNc and VTA groups, RRF neurons have not been widely studied but it is known they project to the dorsal striatum and also connect SNc and VTA neurons (Arts et al., 1996). There have been extensive efforts focused on the generation of mDA neurons from ESC, however, the limited success in this regard is largely due to our still only basic