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How to Make a Midbrain Dopaminergic Neuron Ernest Arenas1,*, Mark Denham1,2 and J

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How to Make a Midbrain Dopaminergic Neuron Ernest Arenas1,*, Mark Denham1,2 and J © 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 1918-1936 doi:10.1242/dev.097394 PRIMER How to make a midbrain dopaminergic neuron Ernest Arenas1,*, Mark Denham1,2 and J. Carlos Villaescusa1,3 ABSTRACT striatum, forming the so-called nigrostriatal pathway, which Midbrain dopaminergic (mDA) neuron development has been an predominantly regulates motor function and degenerates in intense area of research during recent years. This is due in part to a Parkinson’s disease (PD) (Box 1; Fig. 1A and B, in pink). This growing interest in regenerative medicine and the hope that treatment disorder was first described clinically by the British physician for diseases affecting mDA neurons, such as Parkinson’s disease James Parkinson in ‘An Essay of the Shaking Palsy’ published in (PD), might be facilitated by a better understanding of how these 1817 (Horowski et al., 1995). However, it was only many years neurons are specified, differentiated and maintained in vivo. This later that the pathological basis for PD was found to relate to the knowledge might help to instruct efforts to generate mDA neurons degeneration of SNc neurons (Foix and Nicolesco, 1925; Graham, in vitro, which holds promise not only for cell replacement therapy, but 1979; Hassler, 1938) and the loss of dopaminergic innervation of also for disease modeling and drug discovery. In this Primer, we will the striatum (Lloyd and Hornykiewicz, 1970). We now know that focus on recent developments in understanding the molecular PD involves the degeneration of multiple neuronal subtypes mechanisms that regulate the development of mDA neurons in vivo, besides SNc neurons (Jellinger, 1991). However, the cells that are and how they have been used to generate human mDA neurons most affected and responsible for many of the motor features in in vitro from pluripotent stem cells or from somatic cells via direct PD are mDA neurons of the SNc, a cell type that has become a reprogramming. Current challenges and future avenues in the primary target for cell replacement therapy (Box 1). Our ability to development of a regenerative medicine for PD will be identified generate subtype-specific human mDA neurons in vitro might and discussed. therefore hold the key for the development of future regenerative medicine for PD. KEY WORDS: Dopamine neurons, Midbrain, Parkinson’s disease, Transplantation of human fetal midbrain tissue in open-label Regeneration, Reprogramming, Stem cells clinical trials, in which both the researcher and the test subject know what treatment is administered, has provided proof of concept for Introduction cell replacement therapy in PD (Arenas, 2010; Evans et al., 2012; Dopaminergic (DA) neurons are capable of releasing dopamine, a Hallett et al., 2014; Lindvall and Björklund, 2004, 2011). However, catecholaminergic neurotransmitter. They are characterized by the logistical and ethical difficulties in performing such studies using presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in human fetal tissue have led to the search for more amenable cell the synthesis of catecholamines, and are found throughout the preparations that could be standardized for quality, safety and mammalian central nervous system, including the ventral midbrain functionality, prior to clinical use in PD. Human mDA neurons have (VM) (Björklund and Hökfelt, 1983). Midbrain DA (mDA) been generated from multiple cell types in vitro, including neurons are arranged in three distinct nuclei: the substantia nigra neural stem/progenitor cells (NS/PCs) (Maciaczyk et al., 2008; pars compacta (SNc, also known as the A9 group), the ventral Riaz et al., 2002; Ribeiro et al., 2012; Sanchez-Pernaute et al., tegmental area (VTA, or A10 group) and the retrorubral field (RrF, 2001), pluripotent stem cells (PSCs) (Denham et al., 2012; Grealish or A8 group) (Björklund and Hökfelt, 1983; Dahlstroem and Fuxe, et al., 2014; Kirkeby et al., 2012; Kriks et al., 2011; Xi et al., 2012) 1964) (Fig. 1A). Different populations of mDA neurons project and by lineage reprogramming of somatic cells such as fibroblasts to distinct areas and control or modulate specific functions, (Caiazzo et al., 2011; Kim et al., 2011; Pfisterer et al., 2011). The according to their targets [reviewed by Roeper (2013)]. VTA and in vivo functional capacity of PSC-derived mDA cells has recently RrF DA neurons project to the ventromedial striatum (nucleus been found to match that of fetal tissue (Grealish et al., 2014). accumbens), parts of the limbic system and prefrontal cortex, Achieving cell preparations enriched for fully functional human forming the mesolimbic and mesocortical systems (Fig. 1B). SNc DA neurons in vitro and capable of selectively re-innervating These neurons regulate emotional behavior, natural motivation, the dorsal striatum or reconstructing the nigrostriatal pathway is thus reward and cognitive function, and are primarily implicated in a the next challenge. In order to take advantage of the therapeutic range of psychiatric disorders (Carlsson, 2001; Chao and Nestler, potential that stem cells and reprogramming technologies currently 2004; Hornykiewicz, 1978). By contrast, DA neurons located in offer, we must improve our knowledge of the molecular the SNc primarily project to the caudate-putamen, the dorsolateral mechanisms that control mDA neuron development and use this to guide strategies to generate SNc DA neurons and improve 1Laboratory of Molecular Neurobiology, Dept. Medical Biochemistry and functionality in vivo. Biophysics, Center of Developmental Biology for Regenerative Medicine, In this Primer article, we discuss recent advances in 2 Karolinska Institutet, Stockholm 171 77, Sweden. Danish Research Institute of understanding mDA neuron development in vivo, and how Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus 8000, Denmark. 3Institute of Experimental Biology, these developmental principles have and continue to influence the Faculty of Science, Masaryk University, Brno 61137, Czech Republic. development of stem cell therapies. We also outline the challenges *Author for correspondence ([email protected]) and opportunities that lie ahead in order to efficiently generate safe and functional human mDA neuron preparations for cell This is an Open Access article distributed under the terms of the Creative Commons Attribution replacement therapy, as well as for disease modeling and drug License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. discovery. DEVELOPMENT 1918 PRIMER Development (2015) 142, 1918-1936 doi:10.1242/dev.097394 AB ACC HC H DS PFC LS NA PRC A9 LC A8 CNA A10 A8 A10 SNr ERC A9 OT PC D D C A8A9 A10 A8 + A10 A8 - A10 L R C R V V C D E BP mFP DD T MMT IsO Th IsO D Shh C Otx2 Wnt1 L HHTh Gbx2 Fgf8 R Shh + Wnt5a V Shh Shh + Fgf8 D Shh + Wnt5a + Wnt1 Shh + Otx2 Shh + Wnt5a R C Shh + Gbx2 Shh + Wnt5a + Wnt1 V Fig. 1. Distribution of mDA neurons, their projections in the adult mouse brain and the expression of genes important for their development. (A) Coronal section of the adult brain at the midbrain level, showing the position of the three mDA nuclei: RrF/A8, SNc/A9 and VTA/A10. (B) Sagittal view of the adult brain with a schematic representation of mDA neurons and their projection areas. A8, retrorubral; A9, substantia nigra; A10, ventral tegmental area; A8+A10, structures innervated by A8 and A10; A8-A10, structures innervated by A8, A9 and A10; ACC, anterior cingulate cortex; CNA, central nucleus of the amygdala; DS, dorsal striatum; ERC, entorhinal cortex; H, habenula; HC, hippocampus; LC, locus coeruleus; LS, lateral septum; NA, nucleus accumbens; OT, olfactory tubercle; PFC, prefrontal cortex; PRC, perirhinal cortex; PC, pyriform cortex. (C,D) Sagittal view of an E11.5 mouse embryo, showing the expression of transcription factors and morphogens important for VM patterning in relation to Th expression. D, diencephalon; H, hindbrain; IsO, isthmic organizer; M, midbrain; T, telencephalon. (E) Coronal section through the VM at the level shown by arrows in D. BP, basal plate; mFP, midbrain floor plate. mDA neuron development through the coordinated expression and mutual repression of the During gastrulation, a posterior-to-anterior migration of cells transcription factors, Otx2 (orthodenticle homolog 2) in the midbrain takes place at the same time as the three germ layers (mesoderm, and Gbx2 (gastrulation brain homeobox 2) in the hindbrain, endoderm and ectoderm) are formed. At the rostral end of the embryo, (Fig. 1C) (Broccoli et al., 1999; Millet et al., 1999; Wassarman the inhibitors DKK1 (dickkopf 1, a WNT inhibitor), NOG (noggin, a et al., 1997). Otx2 and Gbx2 control the patterning of the MHB by BMP inhibitor), LEFTY1 (left-right determination factor 1, a regulating the expression of two morphogens, Wnt1 (wingless-int1; NODAL inhibitor) and CERBERUS (a multifunctional inhibitor of wingless-type MMTV integration site family, member 1 – Mouse Wnt, BMP and Nodal), which suppress posterior signals and pattern Genome Database) in the midbrain and Fgf8 (fibroblast growth the neural ectoderm, leading to the formation of the anterior neural factor 8) in the hindbrain (Joyner et al., 2000; Rhinn et al., 1998) tube (reviewed by Takaoka et al., 2007). As the development of the (Fig. 1D and Fig. 2, yellow area). Whereas Otx2 is required for neural tube proceeds, two signaling centers are formed: the isthmic the expression of Wnt1 (Puelles et al., 2004; Rhinn et al., 1999), organizer (IsO), which defines the midbrain-hindbrain boundary the induction of Fgf8 requires Pax2 (paired homeobox 2) and is (MHB) (Joyner et al., 2000; Rhinn et al., 1998; Wassarman et al., maintained by Gbx2 (Ye et al., 1998). Importantly, Fgf8, but not 1997), and the floor plate (FP), which controls ventral identities Wnt1, is required (Chi et al., 2003) and sufficient (Martinez et al., (Placzek and Briscoe, 2005) (Fig. 1C). During these and subsequent 1999) for the induction of the IsO.
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