Article

Molecular organization and timing of Wnt1 expression define cohorts of midbrain dopamine neuron progenitors in vivo

Department of Neuroscience, Brown University, Providence, Rhode Island 02903, USA.
The Journal of Comparative Neurology (Impact Factor: 3.51). 10/2011; 519(15):2978-3000. DOI: 10.1002/cne.22710
Source: PubMed

ABSTRACT Midbrain dopamine (MbDA) neurons are functionally heterogeneous and modulate complex functions through precisely organized anatomical groups. MbDA neurons are generated from Wnt1-expressing progenitors located in the ventral mesencephalon (vMes) during embryogenesis. However, it is unclear whether the progenitor pool is partitioned into distinct cohorts based on molecular identity and whether the timing of gene expression uniquely identifies subtypes of MbDA neurons. In this study we show that Wnt1-expressing MbDA progenitors from embryonic day (E)8.5-12.5 have dynamic molecular identities that correlate with specific spatial locations in the vMes. We also tested the hypothesis that the timing of Wnt1 expression in progenitors is related to the distribution of anatomically distinct cohorts of adult MbDA neurons using genetic inducible fate mapping (GIFM). We demonstrate that the Wnt1 lineage contributes to specific cohorts of MbDA neurons during a 7-day epoch and that the contribution to MbDA neurons predominates over other ventral Mb domains. In addition, we show that calbindin-, GIRK2-, and calretinin-expressing MbDA neuron subtypes are derived from Wnt1-expressing progenitors marked over a broad temporal window. Through GIFM and quantitative analysis we demonstrate that the Wnt1 lineage does not undergo progressive lineage restriction, which eliminates a restricted competence model of generating MbDA diversity. Interestingly, we uncover that two significant peaks of Wnt1 lineage contribution to MbDA neurons occur at E9.5 and E11.5. Collectively, our findings delineate the temporal window of MbDA neuron generation and show that lineage and timing predicts the terminal distribution pattern of MbDA neurons.

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    • "It has been shown that when canonical WNT-signaling is stabilized in the FP, SHH expression is abolished and TH+ neurons appear in the hindbrain, suggesting that WNT-signaling may be involved in mdDA neuronal development [38]. As suggested by several studies, the WNT-family member, which could be involved in the early differentiation of mdDA neurons is WNT1 [19], [40], [43], [57]. For instance, in Wnt1 null-mutants, mdDA neurons do not differentiate properly [41] whereas a more caudal expression of WNT1 and stabilized β-catenin in the caudal FP results in an increase in caudal expression of TH, Nurr1, and Pitx3 [38], [41]. "
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    • "Genetic fate-mapping experiments have indicated that both SNc and VTA DA neurons are generated by proliferating progenitors in the ventricular zone (VZ) of the mFP, which can be identified by their expression of two key morphogenic factors, Wnt1 (Brown et al., 2011) and another lipid-modified glycoprotein , Sonic hedgehog (Shh) (Joksimovic et al., 2009b; Blaess et al., 2011; Hayes et al., 2011). Interestingly, Wnt1-expressing progenitors labeled from E7.5 to E13.5 contribute to mDA neurons much more than other cell types in the ventral midbrain (VM), with a similar time-line and extent to SNc and VTA mDA subtypes (Brown et al., 2011). Progenitor cells in the VZ of the mFP, including radial glia-like cells (Bonilla et al., 2008), undergo neurogenesis and give rise to postmitotic migratory cells. "
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