Abstract
During development, mesodiencephalic dopaminergic (mdDA) neurons form into different molecular subsets. Knowledge of which factors contribute to the specification of these subsets is currently insufficient. In this study, we examined the role of Tcf4, a member of the E-box protein family, in mdDA neuronal development and subset specification. We show that Tcf4 is expressed throughout development, but is no longer detected in adult midbrain. Deletion of Tcf4 results in an initial increase in TH-expressing neurons at E11.5, but this normalizes at later embryonic stages. However, the caudal subset marker Nxph3 and rostral subset marker Ahd2 are affected at E14.5, indicating that Tcf4 is involved in correct differentiation of mdDA neuronal subsets. At P0, expression of these markers partially recovers, whereas expression of Th transcript and TH protein appears to be affected in lateral parts of the mdDA neuronal population. The initial increase in TH-expressing cells and delay in subset specification could be due to the increase in expression of the bHLH factor Ascl1, known for its role in mdDA neuronal differentiation, upon loss of Tcf4. Taken together, our data identified a minor role for Tcf4 in mdDA neuronal development and subset specification.
Highlights
Swammerdam Institute for Life Sciences, FNWI, University of Amsterdam, 1098 XH Amsterdam, Abstract: During development, mesodiencephalic dopaminergic neurons form into different molecular subsets
Since basic helix–loop–helix (bHLH) factors are known to be important in mesodiencephalic dopaminergic (mdDA) neuronal development and the E-box protein family is expressed throughout the embryonic brain, we investigated the expression pattern of the E-box factor Tcf4 (E2-2) during development in the brain
At E11.5, Tcf4 showed a very low level of expression in the midbrain area, and its expression pattern was restricted to the ventricular zone (VZ) of both the floor plate (FP) and basal plate (BP)
Summary
Mesodiencephalic dopaminergic (mdDA) neurons are thought to arise from neural progenitors in the ventricular zone (VZ) of the floor plate (FP) and basal plate (BP) of the midbrain from E11.5 onward [1,2,3]. (Mash1), Ngn, Tcf, and Nato, have been shown to be involved in early stages of mdDA neuronal development during fate decision of neural progenitors and later subset specification [14,15,16,17]. The E-box protein family is a small subfamily of the bHLH protein family, and contains 3 family members; Tcf (E2A), Tcf (E2-2), and Tcf (Heb) [18], which are expressed throughout the developing embryo and embryonic brain These proteins are known to bind to a so-called E-box (CANNTG) in the promoter of different genes, and can act as an activating or repressive factor via homo- and heterodimerization with other. We have established the E-box protein Tcf as a novel factor involved in correct development of mdDA neurons
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