Temporal and spatial requirements of Smoothened in ventral midbrain neuronal development

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.

N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development

“…35,125,132 Upregulation of the Wnt-b-catenin signal in the developing ventral midbrain is observed to suppress Hh signaling. 35,125,141 Conversely, the inhibition of Wnt signaling is observed to increase Hh signaling.…”

“…35,125,132 Upregulation of the Wnt-b-catenin signal in the developing ventral midbrain is observed to suppress Hh signaling. 35,125,141 Conversely, the inhibition of Wnt signaling is observed to increase Hh signaling. 35,125 In addition, in the neural tube of the embryo, Wnt signaling induces expression of the cyclin D1, and affects the G1 phase; on the other hand, Hh signaling affects the G2 phase.…”

“…35,125,141 Conversely, the inhibition of Wnt signaling is observed to increase Hh signaling. 35,125 In addition, in the neural tube of the embryo, Wnt signaling induces expression of the cyclin D1, and affects the G1 phase; on the other hand, Hh signaling affects the G2 phase. 104,123,132 These findings suggest that the balance between Wnt signaling and Hh signaling regulates the proliferation and differentiation of NPC.…”

“…104,123,132 These findings suggest that the balance between Wnt signaling and Hh signaling regulates the proliferation and differentiation of NPC. 35,125,141 …”

Definition of a critical spatiotemporal window within which primary cilia control midbrain dopaminergic neurogenesis

“…33,34 Moreover, conditional inactivation of SHH signaling after E9.0 in the Shhpositive progenitor domain results in only transient phenotypes and eventually normal numbers of THpositive neurons. 34,42 Thus, the induction and specification of mDA neurons may have been completed by the time primary cilia and SHH signaling are lost in Kif3a cko mice. Alternatively or in addition, mild defects in the number of mDA progenitors might be compensated for by adjustments in mDA progenitor proliferation and differentiation.…”