Transcriptional control of midbrain dopaminergic neuron development

Abstract

Although loss of midbrain dopaminergic neurons is associated with one of the most common human neurological disorders, Parkinson's disease, little is known about the specification of this neuronal subtype. Hence, the recent identification of major transcriptional determinants regulating the development of these neurons has brought much excitement and encouragement to this field. These new findings will help to elucidate the genetic program that promotes the generation of midbrain dopaminergic neurons. Importantly, these discoveries will also significantly advance efforts to differentiate stem cells into midbrain dopaminergic neurons that can be used for therapeutic use in treating Parkinson's disease.

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

“…However, in this cell line, endogenous levels of MSX1 were not studied [61]. NGN2 is essential for the conversion of Otx2 + precursors into Nurrl + postmitotic DAn, and its ablation dramatically reduces VM DAn numbers [6,17,18,44,46,68]. For the case of MASH1 and NGN2 we have reproduced previous data [34,36] which, together with the data on MSX1 (Fig.…”

“…Nurrl expression in the mouse (cooperating with Pitx3) is critical for the acquisition of the correct DA phenotype (that requires co-expression of TH, AADC, VMAT2 and DAT) [17,22,73,74]. In relation to LMX1B, loss of function studies indicate that is required for the maintenance of VM DAn [75], and more recently it has been involved in patterning [12,18,76]. hVMl cells activate NURR1 and LMX1B during the first week of differentiation (Fig.…”

“…2). Whereas Mashl is a general proneural gene, thought to act in a permissive manner (that is, dispensable, not required nor sufficient for DAn generation), Msxl and Ngn2 are essential for the correct development of VM DAn [6,17,18,23,27,[43][44][45][46][47].…”

“…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.…”

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

“…Second, attempts to rescue rodent models of PD with mDA derived from mouse embryonic stem (ES) cells that have been programmed with developmental regulatory genes have been successful (28)(29)(30). To further improve both of these techniques, it is critical to refine ES cell manipulations to specifically produce SNpc (A9)-type mDA, the neurons that are prominently lost in PD patients (31,32). Thus, defining the embryonic progenitor pools that contribute to distinct subsets of mDA in vivo is an important step toward our understanding and treatment of diseases of the dopamine system.…”