Dopaminergic Neurons and Brain Reward Pathways
2015; Elsevier BV; Volume: 186; Issue: 3 Linguagem: Inglês
10.1016/j.ajpath.2015.09.023
ISSN1525-2191
Autores Tópico(s)Neurogenesis and neuroplasticity mechanisms
ResumoMidbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/β-catenin and sonic hedgehog–Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-β and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases. Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/β-catenin and sonic hedgehog–Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-β and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases. Midbrain dopaminergic (DA) neurons are located in three major nuclei, including the substantia nigra pars compacta (SNpc; A9 group), the ventral tegmental area (VTA; A10 group), and the retrorubral field (A8 group) (Figure 1A). DA neurons in SNpc project to dorsal striatum via the nigrostriatal pathway, and regulate voluntary movement control as part of the basal ganglia circuitry. In contrast, DA neurons in VTA project to nucleus accumbens (ventral striatum), limbic systems, and the prefrontal cortex via the mesolimbic and mesocortical pathways, respectively (Figure 1A). Dopamine released from the nigrostriatal pathway modulates corticostriatal transmission in medium spiny neurons expressing dopamine D1 or D2 receptors, which leads to movement activation or suppression, respectively.1Kravitz A.V. Freeze B.S. Parker P.R. Kay K. Thwin M.T. Deisseroth K. Kreitzer A.C. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.Nature. 2010; 466: 622-626Crossref PubMed Scopus (1229) Google Scholar, 2Calabresi P. Picconi B. Tozzi A. Ghiglieri V. Di Filippo M. Direct and indirect pathways of basal ganglia: a critical reappraisal.Nat Neurosci. 2014; 17: 1022-1030Crossref PubMed Scopus (457) Google Scholar, 3Tritsch N.X. Sabatini B.L. Dopaminergic modulation of synaptic transmission in cortex and striatum.Neuron. 2012; 76: 33-50Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar In Parkinson disease, loss of DA neurons from SNpc is thought to result in overall motor inhibition because of differential effects on D1 and D2 receptor–expressing neurons.1Kravitz A.V. Freeze B.S. Parker P.R. Kay K. Thwin M.T. Deisseroth K. Kreitzer A.C. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.Nature. 2010; 466: 622-626Crossref PubMed Scopus (1229) Google Scholar, 2Calabresi P. Picconi B. Tozzi A. Ghiglieri V. Di Filippo M. Direct and indirect pathways of basal ganglia: a critical reappraisal.Nat Neurosci. 2014; 17: 1022-1030Crossref PubMed Scopus (457) Google Scholar In addition to its role in motor control, recent studies have identified DA input from SNpc to be important for goal-directed behaviors and habit learning.4Faure A. Haberland U. Conde F. El Massioui N. Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation.J Neurosci. 2005; 25: 2771-2780Crossref PubMed Scopus (311) Google Scholar, 5Redgrave P. Rodriguez M. Smith Y. Rodriguez-Oroz M.C. Lehericy S. Bergman H. Agid Y. DeLong M.R. Obeso J.A. Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease.Nat Rev Neurosci. 2010; 11: 760-772Crossref PubMed Scopus (696) Google Scholar, 6Bromberg-Martin E.S. Matsumoto M. Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting.Neuron. 2010; 68: 815-834Abstract Full Text Full Text PDF PubMed Scopus (1398) Google Scholar, 7Seger C.A. Spiering B.J. A critical review of habit learning and the basal ganglia.Front Syst Neurosci. 2011; 5: 66Crossref PubMed Scopus (115) Google Scholar, 8Wang L.P. Li F. Wang D. Xie K. Shen X. Tsien J.Z. NMDA receptors in dopaminergic neurons are crucial for habit learning.Neuron. 2011; 72: 1055-1066Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Moreover, the mode of DA neuron firing (tonic or phasic) appears to predict or modulate distinct aspects of behavior, with abolishment of phasic firing selectively impairing acquisition of cue-dependent learning and leaving other DA-dependent behaviors intact.9Jin X. Costa R.M. Start/stop signals emerge in nigrostriatal circuits during sequence learning.Nature. 2010; 466: 457-462Crossref PubMed Scopus (385) Google Scholar, 10Cagniard B. Beeler J.A. Britt J.P. McGehee D.S. Marinelli M. Zhuang X. Dopamine scales performance in the absence of new learning.Neuron. 2006; 51: 541-547Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 11Cagniard B. Balsam P.D. Brunner D. Zhuang X. Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward.Neuropsychopharmacology. 2006; 31: 1362-1370Crossref PubMed Scopus (198) Google Scholar In contrast to DA neurons in SNpc, DA neurons in the VTA and retrorubral field regulate cognitive functions, including emotion, motivation, reward, and addictive behaviors. Dysfunctions in these neurons have been implicated in psychiatric disorders. Despite the physiological and clinical relevance of midbrain DA neurons and the associated neural circuitry, the mechanisms involved in its establishment and maintenance are not well elucidated. To provide a more comprehensive view of the DA neural circuit at structural and functional levels, a major task has been to uncover the cellular and molecular mechanisms that govern the development of DA neurons and the formation of functional DA neural circuits. Regarding the development of DA neurons, there have been intense interests in the identification of both intrinsic and extrinsic cues that determine cell fate specification, progenitor expansion, and differentiation of DA neurons12Arenas E. Denham M. Villaescusa J.C. How to make a midbrain dopaminergic neuron.Development. 2015; 142: 1918-1936Crossref PubMed Scopus (199) Google Scholar (Figure 1B). The goal is to apply these mechanisms to reprogram fibroblasts and generate large amounts of DA neurons that can be used in cell replacement therapy in Parkinson disease. If successful, these approaches will circumvent many technical and ethical issues related to using human fetal midbrain tissue for transplantation. In addition, investigations into trophic factor signaling in DA neurons have emerged as a promising route of inquiry because of their potential roles in early specification of DA progenitors, the neuroprotective effect of trophic factors against toxic insults, and their concerted activity in the maintenance of the nigrostriatal circuit.13Aron L. Klein R. Repairing the parkinsonian brain with neurotrophic factors.Trends Neurosci. 2011; 34: 88-100Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 14Andressoo J.O. Saarma M. Signalling mechanisms underlying development and maintenance of dopamine neurons.Curr Opin Neurobiol. 2008; 18: 297-306Crossref PubMed Scopus (34) Google Scholar In this review, we summarize our recent studies on the role of Wingless-type MMTV integration site family (Wnt)/β-catenin and sonic hedgehog (Shh)–Smoothened pathways in the development of DA progenitors and DA neurons. We also discuss how trophic support from transforming growth factor (TGF)-β regulates the survival and maturation of DA neurons, and how TGF-β and its downstream signaling mechanisms might have broad implications on the development and maintenance of neural circuits involving DA neurons (Figure 1B). These discussions summarize the emerging recognition of a holistic approach to investigate DA neurons in the context of circuit functions, and provide an important framework for future studies to further elucidate additional mechanisms that control the assembly, connectivity, maintenance, and degeneration in the important neural circuits established by DA neurons. It is now established that midbrain DA neurons are originated from a neurogenic niche in the ventricular zone of the ventral midbrain (vMB), where neurogenesis of DA neurons occurs from approximately embryonic day (E) 9.5 to E14.5 in the mouse embryo. Within this neurogenic niche, the expression of several cell type–specific transcription factors, including Nurr1, Pitx3, En1/2, Otx2, Foxa1/2, Ngn2, and Lmx1a, enable neural stem and progenitor cells to establish proper cell identity, and control a cascade of transcriptional machinery that regulates cell fate and differentiation of DA neurons at the early stages of neurogenesis.15Prakash N. Wurst W. Genetic networks controlling the development of midbrain dopaminergic neurons.J Physiol. 2006; 575: 403-410Crossref PubMed Scopus (113) Google Scholar, 16Smidt M.P. Burbach J.P. How to make a mesodiencephalic dopaminergic neuron.Nat Rev Neurosci. 2007; 8: 21-32Crossref PubMed Scopus (299) Google Scholar DA progenitors that fail to express these transcription factors show aberrant cell identity or undergo accelerated degeneration because of cell death. Conversely, overexpression of Nurr1, Pitx3, and Lmx1a in embryonic stem cells promotes a robust generation of DA neurons with molecular profiles and functional properties that resemble DA neurons in vivo.17Andersson E. Tryggvason U. Deng Q. Friling S. Alekseenko Z. Robert B. Perlmann T. Ericson J. Identification of intrinsic determinants of midbrain dopamine neurons.Cell. 2006; 124: 393-405Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 18Chung S. Hedlund E. Hwang M. Kim D.W. Shin B.S. Hwang D.Y. Kang U.J. Isacson O. Kim K.S. The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons.Mol Cell Neurosci. 2005; 28: 241-252Crossref PubMed Scopus (122) Google Scholar, 19Wagner J. Akerud P. Castro D.S. Holm P.C. Canals J.M. Snyder E.Y. Perlmann T. Arenas E. Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes.Nat Biotechnol. 1999; 17: 653-659Crossref PubMed Scopus (343) Google Scholar In addition to the intrinsic transcriptional programs, extrinsic factors, such as Wnts and Shh, can activate distinct transcriptional cascades necessary for the induction of the DA phenotype. Wnt signaling through the canonical β-catenin pathway controls the activation of Otx2 and Lmx1a/b20Chung S. Leung A. Han B.S. Chang M.Y. Moon J.I. Kim C.H. Hong S. Pruszak J. Isacson O. Kim K.S. Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.Cell Stem Cell. 2009; 5: 646-658Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 21Tang M. Miyamoto Y. Huang E.J. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons.Development. 2009; 136: 2027-2038Crossref PubMed Scopus (81) Google Scholar, 22Prakash N. Brodski C. Naserke T. Puelles E. Gogoi R. Hall A. Panhuysen M. Echevarria D. Sussel L. Weisenhorn D.M. Martinez S. Arenas E. Simeone A. Wurst W. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.Development. 2006; 133: 89-98Crossref PubMed Scopus (209) Google Scholar; however, Shh exerts its effects through Gli transcription factor–mediated induction of Foxa2.23Ferri A.L. Lin W. Mavromatakis Y.E. Wang J.C. Sasaki H. Whitsett J.A. Ang S.L. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.Development. 2007; 134: 2761-2769Crossref PubMed Scopus (233) Google Scholar Although distinct, these extrinsic signals and their intrinsic transcriptional targets functionally interact at multiple levels. At the ligand level, Wnt1 antagonizes Shh signaling to cause down-regulation of Shh expression and its downstream target, Foxa2.24Tang M. Villaescusa J.C. Luo S.X. Guitarte C. Lei S. Miyamoto Y. Taketo M.M. Arenas E. Huang E.J. Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons.J Neurosci. 2010; 30: 9280-9291Crossref PubMed Scopus (163) Google Scholar, 25Joksimovic M. Yun B.A. Kittappa R. Anderegg A.M. Chang W.W. Taketo M.M. McKay R.D. Awatramani R.B. Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis.Nat Neurosci. 2009; 12: 125-131Crossref PubMed Scopus (169) Google Scholar However, forced expression of Wnt1 transcription targets, Lmx1a and Otx2, acts synergistically with Foxa2 to enhance differentiation of DA neurons.20Chung S. Leung A. Han B.S. Chang M.Y. Moon J.I. Kim C.H. Hong S. Pruszak J. Isacson O. Kim K.S. Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.Cell Stem Cell. 2009; 5: 646-658Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 26Nakatani T. Kumai M. Mizuhara E. Minaki Y. Ono Y. Lmx1a and Lmx1b cooperate with Foxa2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon.Dev Biol. 2010; 339: 101-113Crossref PubMed Scopus (98) Google Scholar The interplay between these distinct, yet interdependent, mechanisms and their effects on DA neurogenesis in vivo and in vitro is still not well-elucidated. Several lines of evidence indicate that the ventral region of the developing neural tube contains progenitors that can be divided into a distinct domain on the basis of the expression of cell type–specific transcription factors, which are required for the development of different groups of neurons in the ventral neural tube.27Jessell T.M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes.Nat Rev Genet. 2000; 1: 20-29Crossref PubMed Scopus (1643) Google Scholar, 28Dessaud E. Ribes V. Balaskas N. Yang L.L. Pierani A. Kicheva A. Novitch B.G. Briscoe J. Sasai N. Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog.PLoS Biol. 2010; 8: e1000382Crossref PubMed Scopus (151) Google Scholar, 29Dessaud E. Yang L.L. Hill K. Cox B. Ulloa F. Ribeiro A. Mynett A. Novitch B.G. Briscoe J. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism.Nature. 2007; 450: 717-720Crossref PubMed Scopus (413) Google Scholar Consistent with this idea, several studies have shown that a combinatorial code of cell type–specific transcription factors defines discrete progenitor domains in vMB that are distinctly different from the ventral progenitors in the spinal cord. As early as E8 to E8.5, the expression of transcription factors Lmx1a, Foxa2, Nkx2.1, and Nkx6.1 can be identified in a group of progenitors along the midline of vMB (Figure 2, A and B). As neurogenesis progresses, the DA niche undergoes medial to lateral expansion from E8.5 to E11.5. Unlike the developing spinal cord, the Foxa2+ progenitor domain (D1 and D2 domains) in vMB undergoes a tremendous expansion and shows a transient coexpression with Nkx2.2 at E9.5, followed by a persistent and extensive coexpression with Nkx6.1 from E10.5 to E12.5.26Nakatani T. Kumai M. Mizuhara E. Minaki Y. Ono Y. Lmx1a and Lmx1b cooperate with Foxa2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon.Dev Biol. 2010; 339: 101-113Crossref PubMed Scopus (98) Google Scholar, 30Tang M. Luo S.X. Tang V. Huang E.J. Temporal and spatial requirements of Smoothened in ventral midbrain neuronal development.Neural Dev. 2013; 8: 8Crossref PubMed Scopus (19) Google Scholar, 31Nakatani T. Minaki Y. Kumai M. Ono Y. Helt determines GABAergic over glutamatergic neuronal fate by repressing Ngn genes in the developing mesencephalon.Development. 2007; 134: 2783-2793Crossref PubMed Scopus (90) Google Scholar Together, these results delineate a dynamic expansion of the vMB progenitor domains that are distinctively different from those in the spinal cord. Several members of the Wnt family have been shown to regulate distinct aspects of the development of vMB DA neurons. For instance, the canonical Wnt signaling mechanisms, mediated by Wnt1, Wnt2, and Wnt3a, control the patterning of midbrain-hindbrain boundary and the initial generation of DA progenitors in vMB, whereas Wnt5a regulates the differentiation of DA neurons.32Danielian P.S. McMahon A.P. Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development.Nature. 1996; 383: 332-334Crossref PubMed Scopus (246) Google Scholar, 33Castelo-Branco G. Wagner J. Rodriguez F.J. Kele J. Sousa K. Rawal N. Pasolli H.A. Fuchs E. Kitajewski J. Arenas E. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a.Proc Natl Acad Sci U S A. 2003; 100: 12747-12752Crossref PubMed Scopus (321) Google Scholar, 34Andersson E.R. Prakash N. Cajanek L. Minina E. Bryja V. Bryjova L. Yamaguchi T.P. Hall A.C. Wurst W. Arenas E. Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo.PLoS One. 2008; 3: e3517Crossref PubMed Scopus (82) Google Scholar Results from mouse genetic studies further reveal a network of genetic interactions controlled by Wnt1 to regulate the early expansion of DA progenitors and the differentiation of DA neurons.22Prakash N. Brodski C. Naserke T. Puelles E. Gogoi R. Hall A. Panhuysen M. Echevarria D. Sussel L. Weisenhorn D.M. Martinez S. Arenas E. Simeone A. Wurst W. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.Development. 2006; 133: 89-98Crossref PubMed Scopus (209) Google Scholar Consistent with these results, removal of β-catenin in vMB using Shh-Cre or in DA progenitors and DA neurons using TH-IRES-Cre reveals a critical role of Wnt/β-catenin signaling in cell cycle progression and differentiation during DA neurogenesis.21Tang M. Miyamoto Y. Huang E.J. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons.Development. 2009; 136: 2027-2038Crossref PubMed Scopus (81) Google Scholar, 25Joksimovic M. Yun B.A. Kittappa R. Anderegg A.M. Chang W.W. Taketo M.M. McKay R.D. Awatramani R.B. Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis.Nat Neurosci. 2009; 12: 125-131Crossref PubMed Scopus (169) Google Scholar In addition, β-catenin is prominently expressed in the radial glia processes and shows extensive colocalization with N-cadherin in the adherens junction of DA progenitors.21Tang M. Miyamoto Y. Huang E.J. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons.Development. 2009; 136: 2027-2038Crossref PubMed Scopus (81) Google Scholar Consistent with the important role of β-catenin in the maintenance of adherens junctions, DA progenitors lacking β-catenin show severe disruption of the radial glia process. These results are similar to those reported in mice lacking N-cadherin.35Kadowaki M. Nakamura S. Machon O. Krauss S. Radice G.L. Takeichi M. N-cadherin mediates cortical organization in the mouse brain.Dev Biol. 2007; 304: 22-33Crossref PubMed Scopus (233) Google Scholar Given the important functions of radial glia in neuronal migration during development,36Kriegstein A. Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells.Annu Rev Neurosci. 2009; 32: 149-184Crossref PubMed Scopus (1632) Google Scholar these results support the idea that the interaction between β-catenin and N-cadherin may regulate the migration and final segregation of DA neurons to their final destination in SNpc and VTA. Consistent with the role of Wnt/β-catenin in regulating cell proliferation, constitutive activation of Wnt/β-catenin by stabilizing β-catenin in DA progenitors shortens cell cycle progression and leads to a marked expansion of early DA progenitors that express Sox2, Ngn2, and Otx2, as well as committed DA progenitors that express Lmx1a, Lmx1b, and Nurr1. However, DA progenitors with stabilized β-catenin exhibit reduced, rather than increased, production of mature DA neurons. This phenotype may be because of the perturbations in cell cycle progression in DA progenitors. Alternatively, it is possible that the imbalance in canonical and noncanonical Wnt signaling pathways in DA progenitors may suppress their ability to become mature DA neurons. In support of the latter scenario, DA progenitors expressing stabilized β-catenin are fully capable of differentiating into mature DA neurons in the presence of Wnt5a using dissociated cultures.24Tang M. Villaescusa J.C. Luo S.X. Guitarte C. Lei S. Miyamoto Y. Taketo M.M. Arenas E. Huang E.J. Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons.J Neurosci. 2010; 30: 9280-9291Crossref PubMed Scopus (163) Google Scholar In addition, cell type–specific activation of Wnt/β-catenin in a few Nurr1+ committed DA progenitors using TH-IRES-Cre leads to an increase in Nurr1+ cells and mature DA neurons in prenatal and perinatal brains.24Tang M. Villaescusa J.C. Luo S.X. Guitarte C. Lei S. Miyamoto Y. Taketo M.M. Arenas E. Huang E.J. Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons.J Neurosci. 2010; 30: 9280-9291Crossref PubMed Scopus (163) Google Scholar Together, these results are in agreement with the data from mouse embryonic stem cells that forced expression of Wnt target gene Lmx1a alone can induce a robust up-regulation of Nurr1 and Pitx3, but only a limited number of DA progenitors can differentiate into DA neurons.20Chung S. Leung A. Han B.S. Chang M.Y. Moon J.I. Kim C.H. Hong S. Pruszak J. Isacson O. Kim K.S. Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.Cell Stem Cell. 2009; 5: 646-658Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Collectively, these results support that Wnt/β-catenin signaling provides critical permissive cues to support the expansion, cell cycle progression, and differentiation of DA progenitors. Unlike the diffuse and nondiscrete expression of Wnt ligands, Shh expression is intense in vMB and defines an enriched region that produces a diverse group of neurons, including DA neurons, serotoninergic neurons, and neurons in the red nucleus.30Tang M. Luo S.X. Tang V. Huang E.J. Temporal and spatial requirements of Smoothened in ventral midbrain neuronal development.Neural Dev. 2013; 8: 8Crossref PubMed Scopus (19) Google Scholar, 37Blaess S. Bodea G.O. Kabanova A. Chanet S. Mugniery E. Derouiche A. Stephen D. Joyner A.L. Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei.Neural Dev. 2011; 6: 29Crossref PubMed Scopus (93) Google Scholar, 38Blaess S. Corrales J.D. Joyner A.L. Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region.Development. 2006; 133: 1799-1809Crossref PubMed Scopus (147) Google Scholar, 39Hayes L. Zhang Z. Albert P. Zervas M. Ahn S. Timing of Sonic hedgehog and Gli1 expression segregates midbrain dopamine neurons.J Comp Neurol. 2011; 519: 3001-3018Crossref PubMed Scopus (51) Google Scholar, 40Joksimovic M. Anderegg A. Roy A. Campochiaro L. Yun B. Kittappa R. McKay R. Awatramani R. Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools.Proc Natl Acad Sci U S A. 2009; 106: 19185-19190Crossref PubMed Scopus (91) Google Scholar Consistent with these results, Shh signaling effectors, including Shh receptor Smoothened, Patched, and Gli1, show dynamic changes in vMB from E9.5 to E12.5, whereas the expression of Gli2 and Gli3 is more restricted to the dorsal midbrain. Interestingly, despite the broad expression of Shh signaling effectors in vMB, removal of Smoothened using Shh-Cre results in only a transient reduction in DA progenitors at E10.5 in Shh-Cre;Smofl/fl mutants30Tang M. Luo S.X. Tang V. Huang E.J. Temporal and spatial requirements of Smoothened in ventral midbrain neuronal development.Neural Dev. 2013; 8: 8Crossref PubMed Scopus (19) Google Scholar (Figure 2). The modest and transient loss of DA progenitors and DA neurons in Shh-Cre;Smofl/fl mutants is different from the more severe DA neuron deficits seen in En1-Cre;Smofl/fl and En1-Cre;Shhfl/fl mutants,38Blaess S. Corrales J.D. Joyner A.L. Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region.Development. 2006; 133: 1799-1809Crossref PubMed Scopus (147) Google Scholar, 41Perez-Balaguer A. Puelles E. Wurst W. Martinez S. Shh dependent and independent maintenance of basal midbrain.Mech Dev. 2009; 126: 301-313Crossref PubMed Scopus (41) Google Scholar most likely because of the broader patterning defects caused by En1-Cre in the dorsal midbrain and vMB, which can disrupt the expression of another important patterning gene, FGF8, in the midbrain and hindbrain boundary. Using in vitro cultures and mouse genetics, several groups have shown that the canonical Wnt signaling antagonizes Shh expression during the neurogenesis of DA neurons.21Tang M. Miyamoto Y. Huang E.J. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons.Development. 2009; 136: 2027-2038Crossref PubMed Scopus (81) Google Scholar, 24Tang M. Villaescusa J.C. Luo S.X. Guitarte C. Lei S. Miyamoto Y. Taketo M.M. Arenas E. Huang E.J. Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons.J Neurosci. 2010; 30: 9280-9291Crossref PubMed Scopus (163) Google Scholar, 25Joksimovic M. Yun B.A. Kittappa R. Anderegg A.M. Chang W.W. Taketo M.M. McKay R.D. Awatramani R.B. Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis.Nat Neurosci. 2009; 12: 125-131Crossref PubMed Scopus (169) Google Scholar Similar effects of Wnt and Shh have also been confirmed for the generation of DA neurons from stem cells.20Chung S. Leung A. Han B.S. Chang M.Y. Moon J.I. Kim C.H. Hong S. Pruszak J. Isacson O. Kim K.S. Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.Cell Stem Cell. 2009; 5: 646-658Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Interestingly, analyses of the phenotypes in loss-of-function Shh-Cre;Smofl/fl mutants or the gain-of-function Shh-Cre;SmoM2 mutants indicate that Shh-Smoothened activity has a more dominant effect in regulating the development of DA progenitors at early embryonic stages before E10.5, whereas the effects of the canonical Wnt–β-catenin signaling are much more robust after E12.5. Together, these results support the model that Shh-Smoothened and Wnt–β-catenin signaling has sequential and antagonistic effects in regulating the development of DA neurons. After neurogenesis, the number of DA neurons progressively increases from postnatal day (P) 0 an
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