PMC:1084331 / 27729-29943 JSONTXT

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Calretinin and Calbindin, two different calcium-binding proteins expressed by subpopulations of DRG neurons in wild-type, Er81EWS-Pea3/−, and TauEWS-Pea3/+ PVCre/+ embryos (Figure 7E, 7G, and 7H; data not shown) [31,32], were induced in more than 95% of all DRG neurons of TauEWS-Pea3/+ Isl1Cre/+ embryos (Figures 7F and S5). These findings suggest that DRG neurons in TauEWS-Pea3/+ Isl1Cre/+ embryos fail to differentiate to a normal fate and instead acquire an aberrant identity distinct from any subpopulation of wild-type DRG neurons. Finally, to assess whether EWS-Pea3 expressed precociously acts exclusively cell-autonomously or whether it may also influence neighboring DRG neurons, we activated expression of EWS-Pea3 using Hb9Cre mice [33]. Due to a transient and rostro-caudally graded expression of Hb9 at neural plate stages, very few DRG neurons at brachial levels and increasingly more neurons progressing caudally undergo recombination in TauEWS-Pea3/+ Hb9Cre/+ and TaumGFP/+ Hb9Cre/+ embryos (Figure 8). Nevertheless, downregulation of Trk receptor expression or upregulation of Calretinin is restricted exclusively to neurons that have undergone recombination and cannot be observed in TaumGFP/+ Hb9Cre/+ embryos (Figure 8). Together, these results and the findings obtained from in vitro culture experiments (see Figures 4 and 5) demonstrate that precocious or isochronic expression of EWS-Pea3 in the same neurons leads to significantly different cell-autonomous cellular responses with respect to gene expression, neuronal survival, and neurite outgrowth (Figure 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