Abstract
BackgroundSeveral studies have indicated that Sonic hedgehog (Shh) regulates the expansion of dopaminergic (DA) progenitors and the subsequent generation of mature DA neurons. This prevailing view has been based primarily on in vitro culture results, and the exact in vivo function of Shh signaling in the patterning and neurogenesis of the ventral midbrain (vMB) remains unclear.MethodsWe characterized the transcriptional codes for the vMB progenitor domains, and correlated them with the expression patterns of Shh signaling effectors, including Shh, Smoothened, Patched, Gli1, Gli2 and Gli3.ResultsWhile Shh and its downstream effectors showed robust expression in the neurogenic niche for DA progenitors at embryonic day (E)8 to E8.5, their expression shifted to the lateral domains from E9.5 to E12.5. Consistent with this dynamic change, conditional mutants with region-specific removal of the Shh receptor Smoothened in the vMB progenitors (Shh-Cre;Smofl/fl) showed a transient reduction in DA progenitors and DA neurons at E10.5, but had more profound defects in neurons derived from the more lateral domains, including those in the red nucleus, oculomotor nucleus, and raphe nuclei. Conversely, constitutive activation of Smoothened signaling in vMB (Shh-Cre;SmoM2) showed transient expansion of the same progenitor population. To further characterize the nature of Shh-Smoothened signaling in vMB, we examined the BAT-GAL reporter and the expression of Wnt1 in vMB, and found that the antagonistic effects of Shh and Wnt signaling critically regulate the development of DA progenitors and DA neurons.ConclusionThese results highlight previously unrecognized effects of Shh-Smoothened signaling in the region-specific neurogenesis within the vMB.
Highlights
Several studies have indicated that Sonic hedgehog (Shh) regulates the expansion of dopaminergic (DA) progenitors and the subsequent generation of mature DA neurons
Because the expression patterns of Shh, Patched and Gli1 showed a medial to lateral expansion from E8.5 to E12.5 (Figure 1; Figure 2), we investigated if they might overlap with the ventral midbrain (vMB) progenitor domains
Loss of Smoothened in ventral midbrain affects the generation of neurons in red nucleus, oculomotor nucleus, and raphe nuclei, but not dopaminergic neurons Given the progressively restricted expression of Shh effectors to the lateral domains in vMB, we investigated if the effects of Smoothened loss of function on the progenitors at E10.5 and E12.5 might affect distinct classes of neurons arising from different vMB domains (Figure 2, Figure 3, Figure 5)
Summary
Several studies have indicated that Sonic hedgehog (Shh) regulates the expansion of dopaminergic (DA) progenitors and the subsequent generation of mature DA neurons. This prevailing view has been based primarily on in vitro culture results, and the exact in vivo function of Shh signaling in the patterning and neurogenesis of the ventral midbrain (vMB) remains unclear. Several conditional mutants have been developed to remove Shh or the Shh receptor Smoothened using the Engrail1-Cre (En1-Cre;Smofl/fl) mutation, which targets the mid/hindbrain region [8,17] These mutants show severe defects in the DA neurons, but it remains unclear if these defects are directly due to the effects of Shh in promoting DA neuron development or are caused by the loss of FGF8 and by profound MHB patterning defects in En1Cre;Smofl/fl mutants [18,19,20]. The exact role of Shh signaling in the development of DA and other progenitors in vMB remains unclear
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