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Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons in Vivo and from Stem Cells

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Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons in Vivo and from Stem Cells Journal of Developmental Biology Review Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons In Vivo and from Stem Cells Claude Brodski 1,*, Sandra Blaess 2,*, Juha Partanen 3,* and Nilima Prakash 4,* 1 Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel 2 Institute of Reconstructive Neurobiology, University of Bonn Medical Center, 53127 Bonn, Germany 3 Faculty of Biological and Environmental Sciences, FIN00014-University of Helsinki, P.O. Box 56, Viikinkaari 9, FIN-00014 Helsinki, Finland 4 Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, 59063 Hamm, Germany * Correspondence: [email protected] (C.B.); [email protected] (S.B.); juha.m.partanen@helsinki.fi (J.P.); [email protected] (N.P.); Tel.: +972-8647-7320 (C.B.); +49-228-6885-540 (S.B.); +358-504-485-808 (J.P.); +49-2381-8789-512 (N.P.) Received: 30 November 2018; Accepted: 9 January 2019; Published: 15 January 2019 Abstract: Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson’s Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro. Keywords: dopamine; neuron; FGF8; SHH; WNT; BMP; Parkinson’s disease; pluripotent stem cells; iPSC 1. Introduction The major dopaminergic (DA) neuronal population of the mammalian brain is located in the ventral midbrain (VM) [1]. Confined to a relatively small territory within the VM, mDA neurons are organized into three cell groups, the retrorubral field or A8 group, the substantia nigra pars compacta (SNc) or A9 group, and the ventral tegmental area (VTA) or A10 group [1]. Neurons of the VTA project to the prefrontal cortex to form the mesocortical pathway, which is important for cognition (Figure1)[ 2]. Impairment of the DA output to the prefrontal cortex has been implicated in schizophrenia and attention deficit hyperactivity disorder (ADHD) [3,4]. VTA neurons also send their axons to limbic structures to form the mesolimbic pathway linked to motivation, reward, and addiction behaviors. SNc neurons project to the dorsolateral striatum. These SNc projections constitute the J. Dev. Biol. 2019, 7, 3; doi:10.3390/jdb7010003 www.mdpi.com/journal/jdb J. Dev. Biol. 2019, 7, 3 2 of 34 J. Dev. Biol. 2019, 7, x FOR PEER REVIEW 2 of 34 mesostriataloutput due pathway,to the degeneration a central modulator of the SNc of locomotor DA neurons activity. is the Reduced major striatal cause DAof motor output symptoms due to the degenerationobserved in PD of the(Figure SNc DA1). neurons is the major cause of motor symptoms observed in PD (Figure1). FigureFigure 1.1. TheThe threethree dopaminergicdopaminergic pathwayspathways originatingoriginating inin thethe midbrain.midbrain. Projections,Projections, mainmain functions,functions, andand majormajor disordersdisorders associatedassociated withwith eacheach pathwaypathway areare listedlisted onon thethe left-handleft-hand side.side. AA schematicschematic depictiondepiction ofof thethe correspondingcorresponding humanhuman dopaminergicdopaminergic pathways pathways is is shown shown on on the the right-hand right-hand side. side. TheThe mDAmDA neuronsneurons showshow aa remarkableremarkable diversity,diversity, whichwhich hashas beenbeen recognizedrecognized only recently [[5–7].5–7]. ThisThis diversitydiversity hashas beenbeen describeddescribed inin termsterms ofof theirtheir morphologicalmorphological characteristicscharacteristics [[8],8], genegene expressionexpression patternpattern [[9],9], electrophysiologicalelectrophysiological featuresfeatures [[10],10], andand theirtheir connectivityconnectivity [[11].11]. SuchSuch significantsignificant differencesdifferences areare determineddetermined during during the the development development of the of mDA the mDA neurons. neurons. The molecular The molecular mechanisms mechanisms that underlie that mDAunderlie progenitor mDA proliferation,progenitor proliferation, specification, andspecification, migration, and though migration, not yet fully though understood, not yet appear fully tounderstood, be critical inappear creating to be different critical subsetsin creating of these different neurons. subsets of these neurons. TheThe central central nervous nervous system system in mammals in mammals develop developss from fromthe embryonic the embryonic neural tube, neural which tube, is whichinitially is divided initially into divided four intoparts: four forebrain parts: forebrain(prosencephalon), (prosencephalon), midbrain midbrain(mesencephalon), (mesencephalon), hindbrain hindbrain(rhombencephalon), (rhombencephalon), and spinal and cord. spinal Morphogens cord. Morphogens secreted secretedfrom specific from specificorganizing organizing centerscenters within withinor nearby or nearby the developing the developing neural neural tube guide tube guide the in theitial initial patterning patterning of these of these regions regions andand provide provide the theneural neural stem stem cells cells (NSCs) (NSCs) with with positional positional inform informationation that that directs directs their their development according toto theirtheir location.location. TheThe mDAmDA neuronsneurons developdevelop underunder thethe influenceinfluence ofof thethe midbrainmidbrain FP, containingcontaining SHH-,SHH-, WNT-,WNT-, and and BMP-secreting BMP-secreting cells, cells, and and the the IsO IsO at theat th MHB,e MHB, secreting secreting WNT WNT and and FGFs FGFs from from its rostral its rostral and caudaland caudal border, border, respectively respectively [12]. [12]. FollowingFollowing thethe inductioninduction ofof thethe midbrainmidbrain duringduring embryogenesisembryogenesis [[13],13], aa distinctdistinct mDAmDA progenitorprogenitor domaindomain isis specified specified within within the the midbrain midbrain FP. InFP. this In domain,this domain, radial radial glia-like glia-like neural neural progenitors progenitors divide symmetricallydivide symmetrically to expand to expand their pool their and pool switch and to swit asymmetricch to asymmetric (neurogenic) (neurogenic) divisions divisions at the onset at the of neurogenesisonset of neurogenesis ([14,15] reviewed ([14,15] inreviewed References in [Refere9,12,16nces]). The [9,12,16]). balance betweenThe bala self-renewalnce between and self-renewal cell cycle exitand ofcell the cycle mDA exit neural of the progenitors,mDA neural andprogenitors, the generation and the of generation the appropriate of the numbersappropriate of postmitoticnumbers of progeny,postmitotic is critical progeny, for theis critical proper formationfor the proper of mDA formation neurons. of So mDA far, four neurons. major signalingSo far, four pathways major activatedsignaling by pathways FGFs, SHH, activated WNTs, by and FGFs, BMPs SHH, have WNTs been identified, and BMPs in have mammals been toidentified control the in proliferationmammals to andcontrol specification the proliferation of mDA progenitors and specificationin vivo (reviewed of mDA inprogenitors References [in9,12 vivo,17– 19(reviewed]). Downstream in References of these signaling[9,12,17,18]; pathways, [19]). Downstream expression of of a seriesthese ofsignaling transcription pathways, factors expression (TFs) is activated of a series to regulate of transcription progenitor cellfactors responsiveness (TFs) is activated to these tomorphogens regulate progenitor (OTX2, LMX1A/B,cell responsiveness and FOXA1/2; to these [20 morphogens–28]), neurogenesis (OTX2, (MSX1/2LMX1A/B, and and NGN2; FOXA1/2; [23, 29[20–28]),,30]), and neurogenesis mDA neuron (MSX1/2 differentiation and NGN2; and [23,29,30]), survival and (EN1/2, mDA NURR1, neuron PITX3;differentiation [31–39]). and survival (EN1/2, NURR1, PITX3; [31–39]). Parkinson’sParkinson’s DiseaseDisease (PD)(PD) isis aa prevalentprevalent andand highlyhighly debilitatingdebilitating neurodegenerative disease [[40].40]. ForFor stillstill not not fully fully understood understood reasons, reasons, the SNc the mDA SNc neurons mDA areneurons particularly are particularly vulnerable to vulnerable degeneration to anddegeneration their loss and is a their neuropathological loss is a neuropathological hallmark of hallm PD [12ark]. of Currently, PD [12]. Currently, there is no there cure is for no PDcure and for treatmentsPD and
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