Development of dopaminergic neurons in the mammalian brain

Abstract

Dopaminergic neurons in the mammalian brain have received substantial attention in the past given their fundamental role in several body functions and behaviours. The largest dopaminergic population is found in two nuclei of the ventral midbrain. Cells of the substantia nigra pars compacta are involved in the control of voluntary movements and postural reflexes, and their degeneration in the adult brain leads to Parkinson's disease. Cells of the ventral tegmental area modulate rewarding and cognitive behaviours, and their dysfunction is involved in the pathogenesis of addictive disorders and schizophrenia. Because of their clinical relevance, the embryonic development and maintenance of the midbrain dopaminergic cell groups in the adult have been intensively studied in recent years. In the present review, we provide an overview of the mechanisms and factors involved in the development of dopaminergic neurons in the mammalian brain, with a special emphasis on the midbrain dopaminergic population.

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

“…Human VM neurospheres show a limited expansion capacity, cease to yield DAn (and neurons) with passaging in culture, and in some cases the few DAn present are not born in culture [26,[57][58][59], phenomena also described in rodents [25,60,61]. Adherent human VM FP radial glia cultures cells have been described to maintain their neurogenic potential, but do not differentiate into DAn [20]. Therefore, effort has been put on interventions aimed at enhancing neuron generation [26,58,62].…”

“…VM DAn originate from precursors residing in the mesencephalic floor plate (FP), both in rodents and humans, which show features of radial glia [9][10][11][12], reviewed by [6,[13][14][15][16][17][18][19][20][21][22][23][24]. In spite of the importance of identifying a well-characterized and reliable source of human A9-DAn, the present situation is that all neural stem/precursor cultures explored so far present numerous limitations.…”

Transcriptional control of midbrain dopaminergic neuron development

“…2B and Table 1) have been extensively reviewed elsewhere (Goridis and Rohrer, 2002;Riddle and Pollock, 2003;Wallen and Perlmann, 2003;Simeone, 2005;Smits et al, 2006;Prakash and Wurst, 2006). However, the roles of the transcription factors that govern the specification and early differentiation of mDA progenitors have only recently started to emerge during the past few years and will be the focus of this review (Table 1).…”

Foxa1andFoxa2regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner

“…During phase I, sonic hedgehog (Shh), fibroblast growth factor 8 (Fgf8), Wnt1 and other extrinsic factors control regional and neuronal identity by regulating the expression of Otx2 (Ye et al, 1998;Puelles et al, 2004;Vernay et al, 2005;, Lmx1a (Andersson et al, 2006a), Lmx1b (Smidt et al, 2000), Msx1 and Msx2 (Andersson et al, 2006a), neurogenin 2 (Ngn2; also known as Neurog2 -Mouse Genome Informatics) and Mash1 (also known as Ascl1) (Anderson et al, 2006b;Kele et al, 2006). Subsequently these progenitors undergo an early differentiation step to generate immature mDA neurons expressing Ngn2, Nurr1 (also known as Nr4a2), Lmx1a, Lmx1b, engrailed 1 and engrailed 2 (En1/2) and ␤III-tubulin (Tuj1; also known as Tubb3) (reviewed by Wallen and Perlmann, 2003;Prakash and Wurst, 2006;Smits et al, 2006;Ang, 2006). Immature mDA neurons then further differentiate into mature DA neurons that express tyrosine hydroxylase (TH) and aromatic Lamino acid decarboxylase (AADC), in addition to the other markers mentioned above in immature neurons.…”