Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube

Abstract

The secreted ligand Sonic Hedgehog (Shh) organizes the pattern of cellular differentiation in the ventral neural tube. For the five neuronal subtypes, increasing levels and durations of Shh signaling direct progenitors to progressively more ventral identities. Here we demonstrate that this mode of action is not applicable to the generation of the most ventral cell type, the nonneuronal floor plate (FP). In chick and mouse embryos, FP specification involves a biphasic response to Shh signaling that controls the dynamic expression of key transcription factors. During gastrulation and early somitogenesis, FP induction depends on high levels of Shh signaling. Subsequently, however, prospective FP cells become refractory to Shh signaling, and this is a prerequisite for the elaboration of their identity. This prompts a revision to the model of graded Shh signaling in the neural tube, and provides insight into how the dynamics of morphogen signaling are deployed to extend the patterning capacity of a single ligand. In addition, we provide evidence supporting a common scheme for FP specification by Shh signaling that reconciles mechanisms of FP development in teleosts and amniotes.[Keywords: Shh signaling; neural tube; floor plate; FoxA2] Supplemental material is available at http://www.genesdev.org.

The loss of Hh responsiveness by a non-ciliary Gli2 variant

“…5C). However, as reported previously, Gli1 expression in the floor plate, the ventralmost part of the spinal cord, was downregulated by prolonged exposure to extremely high levels of Shh through a feedback mechanism (Ribes et al, 2010). Gli1 expression was downregulated in the entire Ptch1 mutant spinal cord, consistent with very high levels of Hh pathway activation (Fig.…”

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

“…Conversely, the ectopic pathway activity observed in complete LDA mutants is dependent on the kinetics of SHH ligand production and distribution. Dorsal progenitors in LDA mutants ultimately experience high levels of SHH, as indicated by FOXA2 and NKX2.2 expression; however, dorsal cells may not receive this signal within the narrow early competence window required for definitive floorplate specification (Ribes et al, 2010). Last, additional HH-binding proteins may limit the time and range of SHH ligand-based responses, including the HH co-receptors GAS1, CDON and BOC Izzi et al, 2011), glypicans (Capurro et al, 2008;Li et al, 2011), megalin (LRP2) (Christ et al, 2012), or other cell-surface proteins.…”

“…FOXA2 is crucial for induction of SHH at the ventral midline and its activation there requires the highest level of HH signaling (Ribes et al, 2010;Roelink et al, 1995). In MTPtch1;Ptch1 −/− ;Ptch2 −/− ;Hhip1 −/− embryos, FOXA2 production extends throughout the DV axis with high levels of expression ventrally and low levels dorsally ( Fig.…”

Insights into bird wing evolution and digit specification from polarizing region fate maps

“…5c; as digits 2, 3 and 4 are indistinguishable), digit 5 has a distinct morphology and does not require the longest exposure to Shh to form 23 . Parallels have been drawn between specification of digit 5 and the neural tube floor plate 26 ; the progenitor cells in both cases experience the highest levels of Shh, but downregulate Shh target genes Gli1 and Ptc1 at an early stage 26,27 . Thus digit 5 progenitors, like floor plate progenitors, may be specified by a transient peak of Shh 26 , and this could occur during the time that digits 1 to 4 are being specified by promotion, both outside and inside the polarizing region (Fig.…”