Developmental origin and fate of meso-diencephalic dopamine neurons

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Abstract

Specific vulnerability of substantia nigra compacta neurons as compared to ventral tegmental area neurons, as emphasized in Parkinson's disease, has been studied for many years and is still not well understood. The molecular codes and mechanisms that drive development of these structures have recently been studied through the use of elegant genetic ablation experiments. The data suggested that specific genes at specific anatomical positions in the ventricular zone are crucial to drive development of young neurons into the direction of the dopaminergic phenotype. In addition, it has become clear the these dopaminergic neurons are present in the diencephalon and in the mesencephalon and that they may contain a specific molecular signature that defines specific subsets in terms of position and function. The data indicate that these specific subsets may explain the specific response of these neurons to toxins and genetic ablation.

Introduction

The substantia nigra compacta (SNc) is named after the dark appearance of pigmented dopamine neurons that cluster in this nucleus of the human brain. The selective degeneration of SNc dopamine neurons in Parkinson's disease (PD) indicates that selective vulnerability exists within subgroups of meso-diencephalic dopaminergic (mdDA) neurons (Barzilai and Melamed, 2003). The difference between SNc and ventral tegmental area (VTA) neurons may root in the molecular make-up of these neurons, which originates from specific differentiation routes during development. Recently, several reports have appeared that enlighten this issue. Through ablation studies, genes that are involved in neuronal specification and terminal differentiation have been identified. Interestingly, a Pitx3 null-mutant called aphakia (Varnum and Stevens, 1968, Semina et al., 2000, Rieger et al., 2001) has provided evidence that subsets of mdDA neurons exist which depend differentially on Pitx3 (Smidt et al., 2003, Burbach et al., 2003, Hwang et al., 2003, Nunes et al., 2003, van den Munckhof et al., 2003, Smidt et al., 2004a, Smidt et al., 2004b). These data together with previous analyses of mouse mutants defective in dopaminergic (DA) development have identified several transcription factors involved in mdDA differentiation, with functions in the specification of neurotransmitter identity (Law et al., 1992a, Law et al., 1992b, Zetterström et al., 1997, Saucedo-Cardenas et al., 1998, Smits et al., 2003), neuronal identity and maintenance (Smidt et al., 2000a, Smidt et al., 2000b, Simon et al., 2001).

In this review, we highlight the development of mdDA neurons in view of regional specification, neuronal specification and differentiation. The present data suggest a mechanism that links molecular codes to neuronal identity, number and survival of subsets of mdDA neurons. Moreover, these findings may help to find clues to survival signals of SNc neurons, which may be exploited in PD research.

Section snippets

Dopaminergic cell groups in the central nervous system

The function of mdDA neurons has been implicated in many psychiatric and neurological disorders. Therefore, much attention has gone to this particular cluster of DA cells. These neurons are anatomically and functionally heterogeneous, but distinctly different from other groups of DA neurons that exist elsewhere in the brain. These distinctions are important to appreciate the significance of molecular findings in the mdDA system. In the murine brain, DA neurons are identified in these structures:

Midbrain development: commitment of the mesencephalic area

In order to appreciate the developmental programs of mdDA neurons, it is important to consider the patterning events that occur in the midbrain before DA neurons can be distinguished. Events with consequences for the commitment and position of mdDA neurons can be traced back to very early stages of neural induction. The first step towards generating cellular diversity is the initial subdivision of the neuronal plate in restricted domains. As development progresses, these domains are further

Pitx3 is uniquely expressed in mdDA neurons in the brain

Pitx3, a member of the Pitx subfamily (Lamonerie et al., 1996, Gage and Camper, 1997, Smidt et al., 1997, Semina et al., 1996), was at about the same time identified by two groups. It was cloned by homology screening using Pitx2 (Semina et al., 1997) and by a degenerate PCR strategy from rat brain (Smidt et al., 1997). Pitx3 is transiently expressed in the eye lens and skeletal muscle (E12–E18) and uniquely and constitutively expressed in mdDA neurons. This expression site is maintained until

Expression profiling of mdDA neurons

To identify factors that are expressed in mdDA neurons, the complete expression profile of murine mdDA neurons has been defined by DNA microarray technology (Grimm et al., 2004, Greene et al., 2005, Chung et al., 2005a, Chung et al., 2005b). Despite considerable heterogeneity in cell morphology, electrophysiological properties, connectivity and susceptibility for Pitx3-deficiency and degeneration in PD between mdDA neurons in the SNc and VTA, these neurons are closely related with only <1% (

ES-cell research and implications for replacement therapy in Parkinson's disease

The most prominent progressive neurodegenerative movement disorder, PD, is attributed to selective loss of dopamine neurons in the SNc resulting in severe deficiency of dopamine (Hirsch et al., 1988). Although the use of animal models has provided insights into the etiology and pathogenesis of PD, the cause of sporadic PD remains elusive. The best known pharmacological treatment to date is based on the use of l-DOPA or DA agonists, which are merely substitutive therapies that fail to alter

Concluding remarks

We have summarized the molecular events that are essential for the development and maintenance of mdDA neurons. Although many genes are found to be involved in these processes, the key mechanisms are still not known. The problem has been complicated by the fact that probably the mdDA system is not a homogenous group of neurons. It is possible that a multitude of subsets exist that all have a specific molecular mechanism of development, maintenance and function. Convincing data on the origin of

Note added in proof

A recent paper (Prakash et al., 2006; Development 133 (1), 89–98) was published that nicely describes the role of Wnt-1 on development of the mdDA system.

Acknowledgments

We would like to thank Luis Puelles (Murcia, Spain) for helpful discussions about mdDA neuronal origin.

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