The role of developmental transcription factors in adult ... · midbrain. By surveying recent stud-ies on Foxa1, Foxa2, Nurr1, Pitx3, Otx2, Lmx1a, Lmx1b, and En1/2, the purpose is

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Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Doucet-Beaupré H, Lévesque M. The role of developmental transcription factors in adult midbrain dopaminergic neurons. OA Neurosciences 2013 Oct 01;1(1):3. Co

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The role of developmental transcription factors in adult midbrain dopaminergic neurons

H Doucet-Beaupré1,2, M Lévesque1,2*

AbstractIntroduction Mesodiencephalic dopamine neurons play crucial roles in the control of a variety of brain functions, including voluntary movement and behaviour-al processes such as mood, reward, and attention. Degeneration of meso-diencephalic dopaminergic neurons also represents one of the principal pathological features of Parkinson’s disease. Recent progress led to the identification of transcription factors that are expressed in dopaminer-gic progenitors and are required for their differentiation. The expression of some of these transcription factors persists into adulthood but their ex-act functions in postnatal and adult dopaminergic neurons remain puz-zling. The objective of this review is to gather recent findings on the po-tential roles of Foxa1, Foxa2, Nurr1, Pitx3, Otx2, Lmx1a, Lmx1b, En1, and En2 in the maintenance of dopamin-ergic circuitry throughout adult-hood. This maintenance appears to be underpinned by the continued ac-tion of developmental transcription factors. The loss of functional alleles of Foxa1/2, Nurr1, Pitx3, or En1/2 seriously impairs the survival do-paminergic neurons, affecting pref-erentially the subtantia nigra pars compacta. Moreover, for almost all transcription factors reviewed here, a genetic association to Parkinson’s

disease has been established. Cur-rently, it is unclear how exactly these developmental transcription factors contribute to the maintenance and survival of the dopaminergic system, but one possible mechanism could be related to transcriptional/trans-lational regulation of mitochondrial bioenergetics and biogenesis.Conclusion This review suggests that develop-mental transcriptional networks are essential for maturity maintenance of mesodiencephalic dopaminergic neurons. Much remains to be done to dissect the effects of each devel-opmental transcription factor on the functional properties of mDA neu-rons in adults.

IntroductionOver the last few decades, extensive efforts have been deployed to iden-tify and understand the role of key transcription factors (TFs) mediat-ing mesodiencephalic dopaminergic (mDA) neurons development (Fig-ure 1A–H). The multiple roles of TFs at different embryonic stages have become increasingly clear1,2. Several TFs promote or repress the activity of thousands of genes that trigger the morphological and metabolic transformations. During early de-velopment, the isthmus organizer (a neuroepithelial signalling centre localized at the midbrain–hindbrain boundary) and the floor plate (a ven-tral signalling centre) drive pattern formation and the generation of mDA neurons in the developing embry-os3–6. During the late stages of devel-opment, mDA neurons are organized in three main groups called the sub-stantia nigra pars compacta (SNpc), the ventral tegmental area (VTA),

and the retrorubral field (RRF). Do-paminergic neurons from the SNpc form the nigrostriatal pathway while neurons from the VTA and RRF are associated with the mesolimbic/me-socortical pathways. Degeneration or dysfunctions of these neurons (or subpopulations of these neurons) can lead to severe neurological dis-orders such as Parkinson’s disease (PD), schizophrenia, and addiction7–9.

In addition to their fundamental role during mDA neuron develop-ment, a large number of TFs remain expressed in adulthood while do-paminergic neuronal maturation is completed (Figure 1I—L). Gaining knowledge with regard to this sus-tained expression of developmental TF into later life could provide pre-cious mechanistic insights into the maintenance of mDA neurons. This review summarizes the current data on the transcriptional control of dopaminergic neurons in the adult midbrain. By surveying recent stud-ies on Foxa1, Foxa2, Nurr1, Pitx3, Otx2, Lmx1a, Lmx1b, and En1/2, the purpose is to gain information about the functional significance of each one in the adult midbrain but more importantly is to begin to develop a general understanding of how these developmental TFs contribute to maintenance and survival of the do-paminergic system. We also discuss recent insights into the role of these TFs in mitochondrial transcriptional regulation and their potential impli-cations in PD.

DiscussionThe authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics

* Corresponding Author E-mail: [email protected] Departement of psychiatry and neuroscienc-

es, Faculty of Medicine, Université Laval, Québec, QC, Canada

2 Centre de recherche de l’Institut universitaire en santé mentale de Québec, 2601, Chemin de la Canardière, Québec, QC, Canada, G1J 2G3

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e.and Lmx1b21 and subsequently con-tinue to function cooperatively with them22. Loss-of-function studies revealed that Foxa1 and Foxa2 are also important for maturation of mDA neurons by regulating Nurr1 and En1 in immature mDA neurons. During early and late differentiation stages of mDA neurons, they regu-late the expression of Pitx3, tyrosine hydroxylase (TH), dopamine trans-porter (DAT), vesicular monoamine transporter 2 (VMAT2), and aro-matic L-amino acid decarboxylase (AADC)18,22–25.

and Foxa2 are expressed in a wide domain in ventral mesodiencephalic progenitors15–17. Foxa1 and Foxa2 are known to play a central role at vari-ous steps of mDA neuron develop-ment. Initially, they are required, in a gene dosage-dependent manner, for specification of mDA progeni-tors18,19. They regulate expression of sonic hedgehog (Shh) signalling components20,21 and neurogenesis by controlling neurogenin 2 (Ngn2) expression18. They participate in mDA neurons differentiation by controlling the expression of Lmx1a

committees related to the institution in which they were performed.

Foxa1 and Foxa2The forkhead box protein A (Foxa) family of transcription factors partic-ipate in transcriptional programmes governing embryonic development and organogenesis of a number of metabolic and endocrine-related tis-sues10,11 including the brain12,13. In mammals, the Foxa subfamily has three members: Foxa1, Foxa2, and Foxa3 (previously termed, HNF3α, HNF3β, and HNF3γ)14 but only Foxa1

Figure 1: Schematic overview showing the expression pattern of key transcription factors during mDA neurons development and in ventral midbrain of adult mouse. A, Representation of a mouse embryo at E12.5 and a section at midbrain level (dashed red line). Ventral midbrain region is boxed and magnified in B. The generation of mDA neurons from neural progenitors follows three sequential steps defining mDA lineage into mDA progenitors, immature neurons, and mature neurons (B). Foxa1/2, Otx2, Lmx1a/b, and En1/2 genes are already expressed in mDA progenitors by E9.5 and their expression persists in both immature and mature mDA neurons (C-F). At E12.5, only a fraction of postmitotic mDA neurons express Otx2 (D)128 Nurr1 expression is initiated in immature postmitotic mDA neurons (G) whereas Pitx3 appears only in mature mDA neurons (H). Note that Otx2, En1/2, Foxa1/2 are present in other non-DA cell populations in ventral midbrain18,20,128,154. Some cells outside mDA domain also express Nurr1. A midbrain section from adult mouse is illustrated in I and the dashed box is magnified in J–L to show expression of the different transcription factors in VTA and SNpc. Nurr1, En1/2, Lmxa/b, and Foxa1/2 genes remain expressed in adult mDA neurons of both VTA and SNpc (J) while Otx2 is only present in central and ventral portion of the VTA (K). Pitx3 gene is expressed in both VTA and SNpc (L)61,155, but protein levels appear lower (or absent) in dorsal SNpc and in scattered mDA neurons in VTA71.

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postmitotic and mature mDA neu-rons42,48. Conditional inactivation of Nurr1 in postmitotic mDA neurons during late development resulted in rapid loss of striatal dopamine, loss of mDA markers, and neuron degen-eration. A similar but slower pro-gressing loss of striatal dopamine and mDA axonal markers was ob-served following ablation of Nurr1 in adult brain42. Nurr1 deletion in ma-ture mDA neurons produced a more severe loss of dopamine neurons in the SNpc than in the VTA and conse-quently engendered a Parkinson’s-like phenotype42. Moreover, Nurr1 ablation specifically in adult mice re-sults in a distinct fibre pathology that affects both dendrites and axons49.

Nurr1 heterozygous mutant mice are more vulnerable to injury induced by MPTP, the classic toxin-induced animal models of PD50 and to toxic-ity of methamphetamine exposure51. The role of Nurr1 in the maintenance of mDA neurons is also highlighted by the identification of several mutations in the genes associated with PD52–56. To identify Nurr1-regulated genes in ma-ture DA neurons, Kadkhodaei et al.49 performed gene expression profiling on conditional Nurr1 gene-targeted mice. Nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulat-ed target genes49. Nuclear-encoded mitochondrial genes and mRNA lev-els of each oxidative phosphorylation component are relevant for mito-chondrial regulation and energy pro-duction. Long-and short-term axon survival depends on mitochondria57 and since Nurr1 targets several nu-clear-encoded mitochondrial genes, deregulation of axonal mitochondrial functions might contribute to the pro-gressive retrograde degeneration of mDA neurons in Nurr1-ablated adult mice. Further studies are required to elucidate this issue.

Pitx3The Pitx3 gene encodes a homeobox bicoid-like transcription factor Pitx3

mDA neurons but rather to the loss of their dopaminergic properties25. Further studies looking at specific inactivation of Foxa1/2 in adult mDA neurons would be necessary to fully elucidate the role of these TFs in the maintenance of mDA neurons.

Nurr1The Nuclear receptor related 1 (Nurr1 also known as NR4A2) gene encodes an orphan member of the steroid/thy-roid hormone receptor super family. These orphan receptors are a group for which endogenous ligands do not exist or have not been identified yet. Nurr1 is an immediate early gene ac-tivated in response to extracellular stresses31,32, which is predominantly, but not exclusively expressed in the brain33. In the developing central nerv-ous system, Nurr1 is primarily known for its association with mDA neuron differentiation33–36. Nurr1-defficient mice result in the absence of mDA neurons37–38. Nurr1 directly transacti-vates the promoter activity of the TH gene in a cell type-dependent man-ner and is, for that reason, necessary for the region-specific expression of TH in mDA neurons39. Nurr1 could be defined as a master regulator in the induction of the neurotransmitter phenotypic identity of mDA neurons1. In addition to TH regulation, Nurr1 also controls the expression of sev-eral key proteins that are necessary for the synthesis and regulation of dopamine including DAT, VMAT2, and AADC40–45. A cross-regulatory model, between Nurr1 and the well-known Wnt/β-catenin signalling components have been described in the develop-ment of the mDA system46. Similarly, nuclear fibroblast growth factor re-ceptor 1 (FGFR1) signals have been reported to partner with Nurr1 in de-veloping postmitotic and mature mDA neurons 47.

Expression of Nurr1 in mDA neu-rons of the SNpc and VTA is main-tained in adult life and appears to be critical for the maintenance of a dopaminergic phenotype in both

Foxa1 and Foxa2 remain expressed into adulthood12,13 but their ex-act roles in the adult brain remain largely unknown. Loss-of-function studies in mice have, however, dem-onstrated the requirement of Foxa2 in the maintenance of mDA neurons. Foxa2 heterozygous mutant mice spontaneously develop significant motor problems and an associated late-onset degeneration of mDA neu-rons. The initial deficit is asymmetric and preferentially affects dopamine neurons of the SNpc23 while leaving the VTA intact23. The loss of a single functional allele does not compro-mise the development of mDA neu-rons but impairs their survival in the postnatal and adult brain. It is possible that Foxa1 and Foxa2, while redundant during development, have evolved divergent roles in the mature brain. A comparable hypothesis has recently been confirmed in the liver for these two TFs26. If this is the case in mDA neurons, it might explain the deficient compensation observed in adulthood.

Similar to what it is observed in human patient with PD, nigral do-paminergic neurons are the first to degenerate in Foxa2 heterozygous mutant mice. Based on anatomical reports showing an impressive differ-ence in axonal arborisation between mDA neurons from SNpc and VTA27–29, it is reasonable to speculate that SNpc neurons have a higher energetic de-mand and are likely more vulnerable to metabolic changes. Loss of a single Foxa allele could result in a reduced capacity to withstand endogenous cell stress, which could further cause a progressive cell loss30.

The contribution of Foxa1 and Foxa2 to the maintenance of mDA neurons is also stressed by a recent in vivo study in which Foxa1 and Foxa2 were specifically deleted in postmitotic mDA neurons. In these animals, a significant reduction of TH-positive neurons in the SNpc was observed. Surprisingly, this diminu-tion is not attributed to the death of

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by Pgc-1α84. Over-expression of Pgc-1α in the SNpc unexpectedly re-sults in dopamine depletion associ-ated with lower levels of Pitx3 and enhances susceptibility to MPTP82. While the authors were exploring the efficacy of Pgc-1α as a therapeu-tic target, the forced expression of Pgc-1α probably disrupts the fine-tune regulation of metabolic activ-ity in the mitochondrial expression/energy balance network. These metabolic changes induced by Pgc-1α could also be explained by an in-direct regulation of Pitx3.

An important negative regulatory relationship has also been uncovered in which Pitx3 regulates miR-133b transcription, a conserved micro-RNA. This latter, in turn, was found to suppress Pitx3 expression post-tran-scriptionally to terminate the devel-opmental signals85. It has also been proposed that neurite outgrowth can be regulated by exosome release of miR-133b86. MicroRNAs have been implicated in age-associated decline of organ functions and miR-133b is specifically enriched in the midbrain and deficient in PD patients85.

Several studies have explored the association between polymorphism in PITX3 gene and the manifestation of PD87-94 but this led to inconsist-ent results. A recent meta-analysis of these studies, however, reporting on more than 5000 PD patients and controls, confirmed a significant as-sociation of three single nucleotide polymorphisms (SNPs) in the Pitx3 gene and the risk of PD95. Thus far, the functional significance of these SNPs remains unknown. All SNPs associated with an increased risk of PD are located in intronic sequences (except for one SNP located in the PITX3 promoter96; and should not be confused with disease-causing ami-no acid substitutions. Alternatively, intronic SNPs could act as genetic regulators, being associated with exon skipping events, or may impair transcription, alter splicing, and re-duce mRNA stability96–98.

vulnerable to degeneration induced by MPTP treatment71.

Molecular targets of Pitx3 include TH, DAT, and VMAT272–74. Interest-ingly, these genes are also targets of Nurr1 and Foxa1/2 (see previous sections). Functional cooperation between Nurr1 and Pitx375,76, be-tween En1 and Pitx377, and between Foxa1/2 and Nurr125 have also been reported. Alternatively, both Nurr1 and Foxa1/2 have been shown to regulate Pitx325,78. Two neurotrophic factors, BDNF (brain derived neu-rotrophic factor) and GDNF (glial cell line derived neurotrophic fac-tor), are also regulated by Pitx379. Moreover, GDNF acts as an upstream stimulatory factor of Pitx380. In cul-tured cells, over-expression of Pitx3 increased the mRNA and protein levels of BDNF and GDNF79. The in-terplay between Pitx3, GDNF, and BDNF appears different during pre- and postnatal stages80. In the adult brain, striatal uptake and retrograde axonal transport of GDNF from axon terminals to the soma, maintains the proper levels of Pitx3 and BDNF ex-pression in SNpc mDA neurons80. As the main known function of BDNF throughout adulthood is to enhance synaptic transmission, facilitate syn-aptic plasticity, and promote synaptic growth81, it might contribute to the synaptic maintenance of nigrostri-atal mDA neurons over the course of aging.

Interestingly, Clark et al.82 found that over-expression of Peroxisome proliferator-activated receptor gam-ma co-activator-1 alpha (Pgc-1α) down-regulates Pitx3 expression in the SNpc82. Pgc-1α has been shown to positively regulate the expression of genes required for mitochondrial biogenesis and the cellular antioxi-dant responses, and also to have a newly discovered role in the forma-tion and maintenance of dendritic spines and synapses83. Nigral do-paminergic neurons are critically sensitive to the modifications in mitochondrial homeostasis induced

(previously named Ptx3). During embryogenesis, Pitx3 is transiently present in the eye lens and in skeletal muscles, but constantly expressed from E11.5 in mouse mDA neurons where it plays an important role in dopaminergic differentiation58,59. The expression pattern of Pitx3 is close to the expression pattern of TH60. After birth, Pitx3 expression is confined to mDA neurons in mammals61.

The Pitx3-deficient aphakia mouse strain, discovered in the 1960s, has facilitated the analysis of the func-tion of the Pitx3 TF during develop-ment62. Although Pitx3 is selectively expressed in mDA neurons of both SNpc and VTA, it is the neurons from the SNpc that are mainly affected in mutant mice lacking Pitx3, while the VTA appears much less affect-ed58–60,63–65. The differential depend-ence of mDA neurons on Pitx3 has been associated to the downstream target gene Aldehyde dehydroge-nase 2 (Ahd2, also known as Raldh1) which is crucial for the enzymatic production of retinoic acid66. Retinoic acid is a pleiotropic activation factor that has several essential functions during brain development that are likely to persist into postnatal life67. The main Ahd2 expression site in the brain is a subpopulation of do-paminergic cells within the SNpc and adjoining VTA68,69. Retinoic acid also exerts anti-apoptotic and antioxidant activities70 and may explain, in part, the role of Pitx3 in the survival of the SNpc mDA neurons. The depend-ence on Pitx3 for the survival of do-paminergic neurons is however not uniform between all mDA neurons. A recent study using mice with hy-pomorphic alleles of Pitx3 (aphakia) supports the existence of distinctive dopaminergic neuronal population with different degrees of suscepti-bility to neurodegeneration71. A sub-set of dopaminergic neurons within SNpc is preserved in Pitx3-deficient mice, indicating that not all mDA neurons require Pitx3 for their sur-vival. These neurons also seem less

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were identified, including the glu-cocorticoid receptor DNA binding factor (GRLF1) and Myosin 1c (MY-O1C), two proteins link to neurite outgrowth, and a stress marker, the heat-shock protein 70 (HSP70)124. Lmx1b has been found in the Nurr1 transcriptional complex suggesting that Lmx1b may act directly in the transcriptional activation of Nurr1 target genes124.

Interestingly, in central serotoner-gic (5-HTergic) neurons, utilization of an inducible Cre-LoxP system to selectively inactivate Lmx1b expres-sion in the raphe nuclei of adult mice, revealed that Lmx1b was required for the biosynthesis of 5-HTergic receptor, and it may be involved in maintaining normal functions of cen-tral 5-HTergic neurons by regulat-ing the expression of Tph2, Sert, and Vmat2125. There is no comparable data for the mDA neurons.

Polymorphisms in LMX1A and LMX1B have previously been linked to PD126 as well as with schizophre-nia127. In search of a possible asso-ciation between schizophrenia and SNPs in three dopamine-related transcription factors, LMX1A, LMX1B and PITX3, Bergman et al.127 found five SNPs that were more common in subjects with schizophrenia which were the same as those previously shown to be over represented in sub-jects with PD87,91,92,96,126. Studies aim-ing to elucidate the role of Lmx1a and Lmx1b in adult mDA neurons as well as to identify the molecular mecha-nisms regulated by these factors in the maintenance of mDA neurons are still lacking.

Otx2Otx2 is a member of the bicoid sub-family of the homeodomain transcrip-tion factor. It has been demonstrated that Otx2 regulates mDA neurogenesis and subtype identity in VTA128,129. Otx2 might directly or indirectly control the activation of Lmx1a and succeed-ing steps of proliferation and differ-entiation of mDA progenitors130,131.

tion and maintenance of midbrain–hindbrain boundary, or isthmic or-ganizer115. Lmx1a and Lmx1b show similar roles in mDA neuron devel-opment in gain-of-function stud-ies in mouse embryos22,24 and in ES cells116. Lmx1b can, partially rescue roof plate development in dreher (Lmx1a) mice, indicating that Lmx1b has some functional redundancy to Lmx1a during development105. More recently, by studying the phenotype of double mutants for Lmx1a and Lmx1b, functional cooperation has been demonstrated between Lmx1a and Lmx1b in regulating prolifera-tion, specification, and differentia-tion of mDA pro genitors109,112.

The co-expression of Lmx1a and Lmx1b persists in mature dopamin-ergic neurons of the SNpc and VTA throughout birth and into adult-hood117,118. Their independent and/or combinatory functions in the adult midbrain remain unknown. Gene profiling analysis of LMX1A overex-pressing MN9D dopaminergic cells allowed for the identification of pu-tative downstream targets of Lmx1a, including Grb10, Rgs4, and Vmat2, and also 13 mitochondrial nuclear-encoded structural subunits of the mitochondrial respiratory chain119.

Developmental studies of knock-out and conditional mutant mice re-vealed that Lmx1b regulate Fgf8 and Wnt1, which are essential for the in-ductive action of the isthmic organiz-er109,117,120–122. Lmx1b expression also precedes the expression of Nurr1, TH, and Pitx3. Consequently, directly targeted genes by Lmx1b during de-velopment are difficult to circum-scribe. Genes under the control of Lmx1b during adulthood are not confirmed yet. A microarray analy-sis using a tetracycline-inducible LMX1B expression system in HeLa cells has revealed that Lmx1b binds to the proximal promoter of IL-6 and IL-8 and activate the nuclear factor-κB (NF-κB)123. In an open search for binding partners of Lmx1b in mDA neurons, new possible interactors

Lmx1a and Lmx1b Lmx1a and Lmx1b genes encode LIM-homeodomain (LIM-HD) pro-teins, a subfamily of transcription factors that have been well-pre-served throughout evolution. The characteristic features of LIM-HD proteins are two specialized zinc fin-gers, called LIM domains, which are recognized by a number of co-factors. According to the co-factors, com-plex formation could either lead to transcriptional activation or repres-sion99. The mouse Lmx1a and Lmx1b proteins share an overall 64% iden-tity in amino acid sequences (100% identity in their HD and 67% and 83% identity in each LIM domain)99. Lmx1a is widely expressed in the de-veloping embryo, including the roof plate of the neural tube, the cerebel-lum, ventral midbrain, otic vesicles, inner ear, the notochord, and the developing pancreas100–102. Lmx1a spontaneous mutantsdreher (Lmx-1adr/dr) exhibit a complex phenotype, including circling behaviour, sterility, pigmentation, and tail abnormali-ties103–106. Lmx1b is required for the normal development of dorsal limb structures, the glomerular basement membrane in the kidney, the ante-rior segment of the eye, skull devel-opment as well as dopaminergic and serotonergic neurons107. Mutations in the human LMX1B gene have been demonstrated to be responsible for the nail-patella syndrome, an auto-somal dominant disorder charac-terized by dysplasia of the patellae, nails, and elbows and focal segmen-tal glomerulosclerosis108.

During midbrain development, Lmx1a and Lmx1b are among the first markers that identify the mDA precursors, and are key regulators of their differentiation109–113. Lmx1a is an efficient inducer of mDA neu-rons from embryonic stem cells114. Loss- and gain-of-function studies in chick embryos demonstrated that Lmx1a is an essential determinant of mDA neuron development110,113. Lmx1b is associated with the forma-

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phenotype at birth but leads a mas-sive mDA neuronal death in SNpc of young adult mice144. Furthermore, a single mutated allele of En1 in an En2 wild-type context, results in a progressive reduction of adult mDA neurons affecting both SNpc and VTA145. En1 and En2 are thus cell-de-pendant – autonomously needed in a gene-dosage – for the maintenance of mDA neurons in the adult brain. Polymorphism in EN1 has also been correlated with PD91. This genetic association suggests a role for EN1 in long-term maintenance of human mDA neurons.

In an elegant study, Alvarez-Fisher et al.146 shed light into the putative mechanism by which En1/2 oper-ate in adult neurons. En1/2 might participate in the local energetic metabolism of adult mDA neurons by regulating the translation of nuclear-encoded subunits of mito-chondrial complex I (NDUFS1 and NDUFS3) and the enzymatic activity of this complex. In vitro and in vivo experiments of this study, demon-strated that exogenous En1/2 could protect nigrostriatal mDA neurons. Infusion of En1/En2 into the SNpc and VTA protected mDA neurons against MPTP and rotenone toxic-ity146. Ndufs1 translation is part of this En1/2-mediated neuroprotec-tive pathway. En1/2 were also test-ed in other PD models in vitro and similarly, confirmed their protective action against 6-hydroxydopamine (6-OHDA) and mutated α-synuclein-A30P 2. In En1 mutant mice, expres-sion of Ndufs1 and Ndufs3 was also 30% lower in dopaminergic SNpc neurons compared to other mDA neurons.

Of interest, Engrailed extracel-lular stimulation of isolated axons in cell culture, unexpectedly results in translation of intermediate fila-ment protein, Lamin B2, a protein normally known as a major constitu-ent of the nuclear envelope. Detailed analysis confirmed Lamin B2 trans-lation in axon and its mitochondrial

of adult mDA neurons as well as in the difference in vulnerability of VTA versus SNpc neurons remain to be studied.

Interestingly, the observed de-generation in Otx2 deficient tissues might take its origin from acute per-turbation of energy metabolism since 60% of Otx2 target genes are nucle-ar-encoded mitochondrial mRNAs137. Recent findings put forward that coordinate regulation of the expres-sion of multiple nuclear-encoded mi-tochondrial mRNAs modulate local energy metabolism in the axon138,139. In this regard, one interesting hy-pothesis is that, developmentally act-ing transcription factors are required throughout adulthood as they are key regulators of the axonal energy balance. Although some alternative explanations cannot be eliminated, this possibility accords well with the fact that Nurr1, Lmx1a, Otx2, and En1/2 (see next section) target mR-NAs of nuclear-encoded subunits of mitochondrial complexes.

En1 and En2The role of the homeoprotein En-grailed has been intensively studied in insect and invertebrate develop-ment. Expression of Engrailed al-lows a cell to interpret morphogen gradients, which spread from a com-partment boundary and specify a posterior pattern140. In vertebrates, there are two Engrailed proteins, Engrailed-1 (En1) and Engrailed-2 (En2). These two paralogues play critical roles in patterning and neu-rogenesis during central nervous system development141.

En1/2 are expressed by SNpc and VTA neurons from early development and continuously into adulthood142. Loss-of-function studies revealed the importance of these TFs for mDA neurons maintenance. For example, when all four alleles of En are absent, mutant mice die at birth and mDA neurons are completely absent142,143. Deletion of one allele of En1 and two alleles of En2 results in a normal

Early studies in adult mice showed that elimination of Otx2 expression in the ventral midbrain resulted in a se-lective loss of axonal projection from dopaminergic neurons in the VTA132. It is now known that Otx2 is expressed in the adult mouse brain but only in a specific, functionally distinct, sub-group of neurons of the VTA, i.e., the central and medial-ventral area of the VTA (Figure 1K)128. Studies, in which Otx2 has selectively been ablated from VTA neurons suggest that Otx2 nega-tively regulates the expression of the dopamine transporter DAT and an inverse correlation between Otx2 ex-pression and the glycosylated active form of DAT, glyco-DAT, is observed128. When ectopically expressed in the SNpc, Otx2 suppresses the expression of the glycol-DAT128. It also confers efficient neuroprotection to MPTP tox-icity by suppressing dopamine recap-ture and accordingly the uptake of the neurotoxic cation MPP+133. A recent study showed that a mild over-expres-sion of Otx2 in neurons significantly compensates vulnerability to MPTP and the progressive SNpc neuronal loss caused by En1 haploin sufficiency. Therefore, it is thought that Otx2 and En1 may share similar molecular ba-sis of actions (see next section about En1/2 and the translation of nuclear-encoded subunits of mitochondrial complex I)134.

In other highly metabolically active cells in the adult retina, loss of Otx2 elicits photoreceptor degeneration and could be rescued by constitutive Otx2 expression in Otx2-ablated reti-nas135. In this context, Otx2 ablation results in inflammation and expres-sion of stress genes that lead to apop-tosis. It has been suggested that Otx2 regulates a critical period of plastic-ity in the developing mouse visual cortex and infusion of Otx2 can reo-pen a window of plasticity in adult retina136. In the mature visual cortex, the persistent internalization of Otx2 in a specific group of cells maintained the critical period of plasticity clo-sure136. The role of Otx2 in plasticity

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the changes during senescence are transcriptional regulation through microRNA and TFs, and represent reversals or extensions of develop-mental patterns153.

Conclusion Studies of TF acting during develop-ment of the mDA neurons revealed that many factors like Foxa1/Foxa2, Nurr1, Pitx3, Otx2, Lmx1a/b, and En1/2 remain expressed in adults. The fundamental roles of these TFs in different tissues in maturity main-tenance of cell-specific secretory and metabolic pathways are being more frequently acknowledged and one should expect that mDA-related TFs engage in similar roles.

Reviewing knowledge on the role of Foxa1/2, Nurr1, Pitx3, Otx2, Lmx1a/b, and En1/2 in adult mid-brain supports the idea that: (1) the loss of a functional allele of Foxa2, Nurr1, and En1/2 does not com-promise the development of mDA neurons but seriously impairs their survival in the postnatal and adult brain. Data for gene dosage effect of Lmx1a/b, Pitx3, and Otx2 are, up till now, not available; (2) Loss-of-function studies for Foxa1/2, Nurr1, Pitx3, and En1/2 show a massive do-paminergic cell death preferentially in SNpc while leaving the VTA more or less intact; (3) Cell death in SNpc is concomitant to loss of striatal in-nervations but line of evidences from Nurr1, Pitx3, and En1/2 experiments point towards a specific role of these TFs in axon maintenance throughout adulthood. Alternatively, axon degen-eration might be the earliest feature of metabolic vulnerability; (4) Each developmentally expressed TF tar-gets thousands of genes and initi-ates downstream cascades leading to profound physiological changes. Aside from the midbrain-specific well-known genes that induce the DA phenotype, nuclear-encoded mi-tochondrial genes (and mitochon-drial bioenergetics related genes) have just begun to come into sight

energy-transducing mitochondrial electron transport chain depends upon the interaction of both nuclear and mitochondrial-encoded gene products. Coordinated regulation of the two genomes in distal cellular compartments poses a singular chal-lenge for neurons. Mitochondria dis-tant from the cell body are therefore more vulnerable than their somatic counterparts57.

The action of En1, through the synthesis of lamin B2, on axonal mi-tochondrial size and activity is evi-dence of a local and non-traditional function exertion by TFs in axons147. Local axonal translation of TFs is thought to be involved in long-range retrograde signalling, in maintenance of connectivity with target cells, and in mediating neuronal cell survival. It has been proposed that stimulat-ing the local synthesis of proteins involved in mitochondrial function might be a common mechanism by which target-derived cues support axon maintenance152. In this context, exploring the role of developmental TFs in mature mDA axon, including their implication in local regulation of mitochondrial protein synthesis, would be especially insightful.

PerspectivesA combination of several transcrip-tion factors orchestrates the devel-opment of mDA neurons. These TFs promote the differentiation of sub-populations and specify neural fate. Each neuronal subtype displays a specific gene expression profile and physiological properties that direct the formation of selective connec-tions with appropriate target cells. Neurons of each subtype have dif-ferent size, neurite topology, and plasticity and present differential vulnerability to cell death when ex-posed to moderate or acute stress. Although the development of mDA neurons is tightly regulated, the transition between pre- and post-natal development and the aging process remains unclear. Many of

localization where it regulates mi-tochondrial size and mitochondrial membrane potential, and supports axon survival147. These observations have been done in Xenopus axon, a model far from mammalian midbrain model, but inspire further exploration of the role of En1/2 in mitochondrial activity in axon and axon maintenance throughout adulthood.

Mitochondrial regulation by TFs and potential significance in PD The TFs involved in the develop-ment of mDA neurons that remain expressed in postnatal stages target a wide variety of genes involved in the dopaminergic phenotype. Nurr1, Lmx1a, Otx2, Pitx3, and En1 and En2 also mediate the expression of sev-eral nuclear-encoded mitochondrial genes as well as key genes impli-cated in the mitochondrial metabo-lism. Conditional gene inactivation of these TFs in the mDA neurons results in cell death. A preferential loss of neurons in the SNpc is the pathologi-cal hallmark of PD. Neurons critically depend on mitochondrial energy for their maintenance and mitochondri-al dysfunction has long been impli-cated in the etiopathogenesis of PD. Functional characterization of genes associated with familial variants of PD revealed that several aspects of mitochondrial biology are pertur-bated in PD including mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control148–150.

Recent evidences suggest that axon degeneration may be the earli-est feature of PD17. The loss of dopa-minergic projections is also a general trend observed in conditional mu-tant mouse model for Nurr1, Otx2, Pitx3, En1, and En2. Although some alternative explanations cannot be eliminated, an appealing hypothesis is that a dysfunction of axonal mito-chondria is implicated in selective degeneration of neuronal projections in these TFs-deficient mouse mod-els. Neurons rely on tight regulation of mitochondrial respiration. The

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10. Friedman JR, Kaestner KH. The Foxa family of transcription factors in develop-ment and metabolism. Cell Mol Life Sci. 2006 Oct;63(19-20):2317–28.11. Katoh M. Human FOX gene family (Review). Int J Oncol. 2004 Nov;25(5): 1495–500.12. Besnard V, Wert SE, Hull WM, Whitsett JA. Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns. 2004 Dec;5(2):193–208.13. Ang S-L. Foxa1 and Foxa2 Transcrip-tion Factors Regulate Differentiation of Midbrain Dopaminergic Neurons. In: Pasterkamp RJ, Smidt M, Burbach JP, eds. Development and Engineering of Dopa-mine Neurons: Springer New York, 2009: 58–65.14. Kaestner KH, Hiemisch H, Luckow B, Schütz G. The HNF-3 gene family of tran-scription factors in mice: gene structure, cDNA sequence, and mRNA distribution. Genomics. 1994 Apr;20(3):377–85.15. Monaghan AP, Kaestner KH, Grau E, Schutz G. Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the defini-tive endoderm, chordamesoderm and neuroectoderm. Development. 1993 Nov;119(3):567–78.16. Ang SL, Rossant J. Anterior mesen-doderm induces mouse engrailed genes in explant cultures. Development. 1993 May;118(1):139–49.17. Sasaki H, Hogan BL. HNF-3 beta as a regulator of floor plate development. Cell 1994 Jan 14;76(1):103–15.18. Ferri ALM, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, et al. Foxa1 and Foxa2 regulate multi-ple phases of midbrain dopaminergic neuron development in a dosage-de-pendent manner. Development. 2007 Aug;134(15):2761–9.19. Kittappa R, Chang WW, Awatramani RB, McKay RD. The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol. 2007 Dec;5(12):e32520. Mavromatakis YE, Lin W, Metzako-pian E, Ferri AL, Yan CH, Sasaki H, et al. Foxa1 and Foxa2 positively and negative-ly regulate Shh signalling to specify ven-tral midbrain progenitor identity. Mech Dev. 2011 Jan-Feb;128(1-2):90–103.21. Metzakopian E, Lin W, Salmon-Divon M, Dvinge H, Andersson E, Ericson J, et

heat-shock protein 70; mDA, mesodi-encephalic dopaminergic; GDNF, glial cell line derived neurotrophic factor; GRLF1, glucocorticoid receptor DNA binding factor; LIM-HD, LIM-homeo-domain; Lmx1adr/dr, Lmx1a spontane-ous mutants dreher; MYO1C, Myosin 1c; Ngn2, neurogenin 2; NR4A2 or Nurr1, Nuclear receptor related 1; PD, Parkinson’s disease; RRF, ret-rorubral field; shh, sonic hedgehog; Pgc-1α, peroxisome proliferator-activated receptor gamma co-activa-tor-1 alpha; SNPs, single nucleotide polymorphisms; SNpc, substantia nigra pars compacta; TF, transcrip-tion factor; TH, tyrosine hydroxylase; VMAT2, vesicular monoamine trans-porter 2; VTA, the ventral tegmental area.

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as the major functional category of TF-regulated target genes for Nurr1, Lmx1a, Otx2, Pitx3, and En1/2. Neu-ronal-specific transcriptional regula-tion of mitochondrial bioenergetics and biogenesis has not been the sub-ject of extensive studies and there-fore molecular mechanisms remain to be elucidated. (5) All TFs reviewed here, except Foxa1/2, have a genetic association to PD. Accordingly, this strongly suggests that mDA neuron functional preservation throughout aging is under the influence of devel-opmental TFs.

This review suggests that develop-mental transcriptional networks are essential for maturity maintenance of mDA neurons. Much remains to be done to dissect apart the effects of each developmental TFs on func-tional properties of mDA neurons in adults. Efforts to understand the molecular basis of their actions could provide precious insights into spe-cific mechanisms underlying axon degeneration in neurodegenerative diseases and normal survival of neu-rons through the late stages of life.

AcknowledgementsWe thank the anonymous reviewers for suggestions that improved this article. The authors apologize for not being able to cite the work of all con-tributors to the field. Work performed in the Lévesque lab is supported by grants from the Natu ral Sciences and Engineering Research Council of Can-ada (NSERC), the Fonds de Recherche en Santé du Québec (FRSQ), and the Banting Research Foundation. HDB is funded by a FRSQ scholarship. ML is a FRSQ Chercheur-Boursier.

Abbreviations list5-Htergic, central serotonergic; AADC, aromatic L-amino acid decar-boxylase; Ahd2 or Raldh1, Aldehyde dehydrogenase 2; BDNF, brain de-rived neurotrophic factor; DAT, do-pamine transporter; FGFR1, nuclear fibroblast growth factor receptor 1; Foxa, forkhead box protein A; HSP70,

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The role of developmental transcription factors in adult ... · midbrain. By surveying recent stud-ies on Foxa1, Foxa2, Nurr1, Pitx3, Otx2, Lmx1a, Lmx1b, and En1/2, the purpose is