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Abstract
The basic helix-loop-helix (bHLH) protein family has previously been shown to be involved in the development of mesodiencephalic dopaminergic (mdDA) neurons in the murine midbrain. Specifically, Ngn2 and Mash1 are known to have a role in the specification of neural progenitors in the ventricular zone (VZ) of the midbrain towards an mdDA neuronal cell-fate. Furthermore, other members of the bHLH protein family, the E-box factors, are expressed in the developing midbrain and are thought to have a role in neuronal differentiation. Here we show that the E-box factor Tcf12 is implicated in early and late development of mdDA neurons. Tcf12 is expressed in the midbrain and in young TH-expressing mdDA neurons throughout development. Tcf12lox/lox;En1cre/+ embryos, that lose Tcf12 at ~embryonic day (E)9 throughout the En1 expression domain, have a changed spatial expression of Lmx1a and Nurr1 and a consistent loss of rostral TH expression. Expression of the subset marker Ahd2 is initially delayed, but recovers during development, eventually showing an ~10% increase in AHD2-expressing cells at postnatal day (P)30. Tcf12lox/lox;Pitx3cre/+ embryos, that lose Tcf12 at ~E12 in post-mitotic mdDA neurons, show no effect on the amount of TH-expressing neurons in the developing midbrain. However, similar as to Tcf12lox/lox;En1cre/+ embryos, subset specification is delayed during development. Taken together, we have identified Tcf12 as a novel factor in mdDA neuronal development. It serves a dual function; one in early cell-fate commitment of neural progenitors and one late in subset specification.
Highlights
The mesodiencephalic dopaminergic system is involved in motor control, reward and motivation in the adult brain
Since Tcf12 is known to be important in regulation of proliferation and differentiation of T-cells in the immune system and possibly cortical neurons (Uittenbogaard and Chiaramello, 2002; Wojciechowski et al, 2007) and we detected a delay in mesodiencephalic dopaminergic (mdDA) neuronal specification, we examined the effect on En1cre driven loss of Tcf12 on the proliferation of neural progenitors in the ventricular zone (VZ)
Since rostral TH expression is still affected at E14.5, whereas the presence of PITX3 is restored, we examined the expression of Ahd2, a marker for the rostral mdDA neuronal population and involved in RA dependent Th gene activation (Jacobs et al, 2007, 2011), and Cck, a marker for the caudal mdDA neuronal population (Veenvliet et al, 2013), in order to validate the programming of emerging mdDA neurons in these mutants
Summary
The mesodiencephalic dopaminergic (mdDA) system is involved in motor control, reward and motivation in the adult brain. The function of bHLH proteins depends on their interaction partner and spatio-temporal expression pattern (Powell and Jarman, 2008) Two members of this family, Ngn and Mash, have been show to have a role in the onset of mdDA neuronal development (Andersson et al, 2006a; Kele et al, 2006). Deletion of Ngn leads to a delay of mdDA neuronal development, eventually resulting in an underdeveloped mdDA neuronal population with a loss of TH-expressing mdDA neurons in both VTA and SNc (Andersson et al, 2006a; Kele et al, 2006) This phenotype is partially compensated by its family-member Mash (Kele et al, 2006), indicating that bHLH proteins function together in mdDA neuronal development
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