Abstract
Sonic Hedgehog (Shh) is a ventrally enriched morphogen controlling dorsoventral patterning of the neural tube. In the dorsal spinal cord, Gli3 protein bound to suppressor-of-fused (Sufu) is converted into Gli3 repressor (Gli3R), which inhibits Shh-target genes. Activation of Shh signalling prevents Gli3R formation, promoting neural tube ventralization. We show that cadherin-7 (Cdh7) expression in the intermediate spinal cord region is required to delimit the boundary between the ventral and the dorsal spinal cord. We demonstrate that Cdh7 functions as a receptor for Shh and enhances Shh signalling. Binding of Shh to Cdh7 promotes its aggregation on the cell membrane and association of Cdh7 with Gli3 and Sufu. These interactions prevent Gli3R formation and cause Gli3 protein degradation. We propose that Shh can act through Cdh7 to limit intracellular movement of Gli3 protein and production of Gli3R, thus eliciting more efficient activation of Gli-dependent signalling.
Highlights
The vertebrate neural tube is patterned along the dorsoventral (DV) axis to form different progenitor domains, identified by unique patterns of transcription factor expression and distinct neuronal fates [1]
Unilateral electroporation of SmoM2-encoding DNA in the spinal cord of Hamburger & Hamilton (HH) st. 10 chick embryos led to ectopic upregulation of Cdh7 in SmoM2-expressing cells within the 2 dorsal spinal cord, whereas endogenous Cdh7 expression was downregulated in SmoM2-expressing cells within the intermediate spinal cord
As a result of Sonic Hedgehog (Shh) graded action, the Pax72 region becomes subdivided into the floor plate and five sharply delimited neural progenitor domains ( p3, pMN, p2 –p0), each of them expressing specific transcription factors [2,5,6,29]
Summary
The vertebrate neural tube is patterned along the dorsoventral (DV) axis to form different progenitor domains, identified by unique patterns of transcription factor expression and distinct neuronal fates [1] This DV patterning results from a ventral-to-dorsal gradient of Sonic Hedgehog (Shh), which is complemented by bone morphogenetic proteins (BMPs) and Wnts acting in the dorsal neural tube. As a result of these interactions, Gli3R production and nuclear accumulation are inhibited, and Gli protein is instead targeted for degradation, enhancing Shh signalling levels These results reveal a new mechanism of Shh signalling regulation and help to understand how a highly dynamic spatio-temporal Shh gradient can result in well-defined boundaries of gene expression
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