Abstract
Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.
Highlights
Dopaminergic (DA) neurons are capable of releasing dopamine, a catecholaminergic neurotransmitter
They are characterized by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and are found throughout the mammalian central nervous system, including the ventral midbrain (VM) (Björklund and Hökfelt, 1983)
Deletion of Wnt1 results in the loss of Lmx1a, Nurr1 and Pitx3 in the midbrain FP (mFP) and a complete loss of Midbrain DA (mDA) neurons (Andersson et al, 2013; Prakash et al, 2006). These results indicate that the specification of mDA neurons is controlled by the Lmx1a/b-Wnt1/Ctnnb autoregulatory loop together with Otx1/2 and Foxa1/2
Summary
Dopaminergic (DA) neurons are capable of releasing dopamine, a catecholaminergic neurotransmitter. In the mFP, they form a positive autoregulatory loop (Chung et al, 2009) (Fig. 2, red arrows) required for mDA specification: on one hand β-catenin directly upregulates Lmx1a and Otx2, and, on the other hand, Lmx1a/b directly upregulate each other as well as Wnt1, Msx1 and two key genes involved in mDA neuronal differentiation and survival, Nurr1 (Nr4a2, nuclear receptor 4a2) and Pitx3 (pituitary homeobox 3, or pairedlike homeodomain transcription factor 3).
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