Genetic networks controlling the development of midbrain dopaminergic neurons

Abstract

Recent data have substantially advanced our understanding of midbrain dopaminergic neuron development. Firstly, a Wnt1-regulated genetic network, including Otx2 and Nkx2-2, and a Shh-controlled genetic cascade, including Lmx1a, Msx1 and Nkx6-1, have been unravelled, acting in parallel or sequentially to establish a territory competent for midbrain dopaminergic precursor production at relatively early stages of neural development. Secondly, the same factors (Wnt1 and Lmx1a/Msx1) appear to regulate midbrain dopaminergic and/or neuronal fate specification in the postmitotic progeny of these precursors by controlling the expression of midbrain dopaminergic-specific and/or general proneural factors at later stages of neural development. For the first time, early inductive events have thus been linked to later differentiation processes in midbrain dopaminergic neuron development. Given the pivotal importance of this neuronal population for normal function of the human brain and its involvement in severe neurological and psychiatric disorders such as Parkinson's Disease, these advances open new prospects for potential stem cell-based therapies. We will summarize these new findings in the overall context of midbrain dopaminergic neuron development in this review.

Figure 1. Establishment of the mDA progenitor domain during early stages of mouse neural development

A, cross-sections through the E9.5–10.5 mouse embryonic ventral midbrain depicting the expression domains of the secreted and transcription factors involved in the genetic networks required for the proper establishment of an Aldh1a1-positive (dark blue) mDA progenitor domain. B, the genetic networks required for the proper establishment of an Aldh1a1-positive mDA progenitor domain. Wnt1 (green) together with Shh (black) and Lmx1a (brown) are expressed in the ventral midline (FP) and/or in the adjacent BP of the mesencephalon. These factors positively control a genetic cascade including Otx2 (yellow), required for repression of Nkx2-2 (red) in the BP, and Msx1 (pink), required for repression of Nkx6-1 (turquoise) in the FP. Induction of Lmx1a in the ventral midbrain appears to require Shh. The possible interactions between Lmx1a and Wnt1 are not yet clarified (indicated by the broken arrows and question mark). Wnt1 and Otx2 mutually induce and/or maintain their expression in the ventral midbrain, although neither factor is necessary for it (indicated by the broken arrows). Wnt1 and Fgf8 (grey, not shown) are also engaged in a cross-regulation of their expression, but a strict requirement of Fgf8 signalling for the development of mDA neurons in vivo is uncertain. See text for details.

Figure 2. Determination of the mDA-specific and generic neuronal cell fate in mDA precursors at intermediate stages of mouse neural development

A, cross-sections through the E12.5 mouse embryonic ventral midbrain depicting the expression domains of the secreted and transcription factors involved in the genetic networks required for the differentiation of mDA precursors into mature mDA neurons (dark blue). B, the genetic networks required for the differentiation of mDA precursors into mature mDA neurons. Wnt1 (green) and Lmx1a (brown) continue to be expressed in the ventral midline (FP) and/or in the adjacent BP of the mesencephalon, but Wnt1 expression is now restricted to the VZ/SVZ of the neuroepithelium, whereas Lmx1a is also expressed in the mantle zone containing the postmitotic progeny. At this stage, these factors positively control a genetic cascade including Msx1 (pink), required for expression of Ngn2 (turquoise) in the VZ/SVZ of the ventral midbrain, and probably also Pitx3 (dark blue), although this remains to be shown (indicated by the broken arrow and question mark). Wnt1 may also maintain the expression of En1/2 (dark blue) in postmitotic mDA neurons at these stages. A complementary pathway controlled by Nurr1/Nr4a2 induces the expression of DA biosynthetic enzymes or transporters (Th and Dat/Slc6a3, dark blue) in these cells. Expression of Nurr1/Nr4a2, Pitx3, Th, Dat/Slc6a3, and En1/2 together define the mDA-specific identity of the postmitotic neurons, whereas their generic neuronal properties are regulated by the expression of the proneural factor Ngn2. The possible interactions between Lmx1a and Wnt1 at this stage are unknown (indicated by the broken arrows and question mark). Neither Otx2 (yellow stripes) nor Shh (black stripes) are required for the generation of mature mDA neurons at this developmental stage. Red: Nkx2-2. See text for details.