Sonic Hedgehog (SHH) and WNT proteins are key regulators in many developmental processes, like embryonic patterning and brain development. In the brain, SHH is expressed in a gradient starting in the floor plate (FP) progressing ventrally in the midbrain, where it is thought to be involved in the development and specification of mesodiencephalic dopaminergic (mdDA) neurons. GLI2A-mediated SHH-signaling induces the expression of Gli1, which is inhibited when cells start expressing SHH themselves. To determine whether mdDA neurons receive GLI2A-mediated SHH-signaling during differentiation, we used a BAC-transgenic mouse model expressing eGFP under the control of the Gli1 promoter. This mouse-model allowed for mapping of GLI2A-mediated SHH-signaling temporal and spatial in the mouse midbrain. Since mdDA neurons are born from E10.5, peaking at E11.0–E12.0, we examined Gli1-eGFP embryos at E11.5, E12.5, and E13.5, indicating whether Gli1 was induced before or during mdDA development and differentiation. Our data indicate that GLI2A-mediated SHH-signaling is not involved in mdDA neuronal differentiation. However, it appears to be involved in the differentiation of neurons which make up a subset of the red nucleus (RN). In order to detect whether mdDA neuronal differentiation may be under the control of canonical WNT-signaling, we used a transgenic mouse-line expressing LacZ under the influence of stable β-catenin. Here, we show that TH+ neurons of the midbrain receive canonical WNT-signaling during differentiation. Therefore, we suggest that early SHH-signaling is indirectly involved in mdDA development through early patterning of the midbrain area, whereas canonical WNT-signaling is directly involved in the differentiation of the mdDA neuronal population.
SummaryMesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies. Key words: Brain, Development, Dopamine, Epigenetics, Gene regulation, Midbrain IntroductionIf you turn this page, both the decision you make and the action that you carry out are significantly influenced by the amount of dopamine (DA; see Glossary, Box 1) released from dopaminergic neurons within your brain. Mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra pars compacta (SNc; see Glossary, Box 1), in particular, are essential for motor functions whereas mdDA neurons of the ventral tegmental area (VTA; see Glossary, Box 1) and the retrorubal field (RRF; see Glossary, Box 1) are involved in the regulation of emotions and reward . Notably, severe loss of SNc mdDA neurons is a pathological hallmark of Parkinson's disease (PD) (Sulzer, 2007). By contrast, mdDA neurons in the VTA and RRF, which remain intact in PD, are part of the mesocorticolimbic system (see Glossary, Box 1), in which defective DA neurotransmission has been implicated in the development of drug addiction, depression and schizophrenia (Nestler, 2000). Given their involvement in neurodegenerative diseases and psychiatric disorders, mdDA neurons have been studied intensively in recent years.In the last two decades, a variety of molecular approaches have revealed factors that are specific for mdDA neuronal subsets or that guide their spatial organization ; recently, a pathway that molecularly distinguishes SNc DA neurons from those located in the VTA was identified (Jacobs et al., 2011). In addition to molecular profiling of DA neurons, however, a second level of complexity has been added by the rapidly emerging field of epigenetics, which has provided new insights into the origin and maintenance of distinctive gene expression patterns in mdDA neurons. Current definitions of epigenetics often emphasize the heritability of changes in gene expression throughout cell divisions that are not due to alterations in DNA sequence. However, perhaps a more appropriate definition of epigenetics, especially when applying this term to mature neurons that cannot divide, is postulated by Adrian Bird: 'The structural adaptation of chromosomal regio...
The basic helix-loop-helix (bHLH) protein family has previously been shown to be involved in the development of mesodiencephalic dopaminergic (mdDA) neurons in the murine midbrain. Specifically, Ngn2 and Mash1 are known to have a role in the specification of neural progenitors in the ventricular zone (VZ) of the midbrain towards an mdDA neuronal cell-fate. Furthermore, other members of the bHLH protein family, the E-box factors, are expressed in the developing midbrain and are thought to have a role in neuronal differentiation. Here we show that the E-box factor Tcf12 is implicated in early and late development of mdDA neurons. Tcf12 is expressed in the midbrain and in young TH-expressing mdDA neurons throughout development. Tcf12lox/lox;En1cre/+ embryos, that lose Tcf12 at ~embryonic day (E)9 throughout the En1 expression domain, have a changed spatial expression of Lmx1a and Nurr1 and a consistent loss of rostral TH expression. Expression of the subset marker Ahd2 is initially delayed, but recovers during development, eventually showing an ~10% increase in AHD2-expressing cells at postnatal day (P)30. Tcf12lox/lox;Pitx3cre/+ embryos, that lose Tcf12 at ~E12 in post-mitotic mdDA neurons, show no effect on the amount of TH-expressing neurons in the developing midbrain. However, similar as to Tcf12lox/lox;En1cre/+ embryos, subset specification is delayed during development. Taken together, we have identified Tcf12 as a novel factor in mdDA neuronal development. It serves a dual function; one in early cell-fate commitment of neural progenitors and one late in subset specification.
The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.
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