Contributions of Noncanonical Smoothened Signaling During Embryonic Development.

Stacey Ogden,Tanushree Pandit

doi:10.3390/jdb5040011

Stacey Ogden, Tanushree Pandit

Open Access

https://doi.org/10.3390/jdb5040011

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Abstract

The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein–independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription-independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease.

Highlights

During embryogenesis, the Sonic Hedgehog (Shh) signal transduction network instructs cell fate decisions to drive tissue patterning
We will instead focus on Gli-independent Smo signaling, and discuss the comparatively limited body of work centered on contributions of this noncanonical signaling effector route during embryonic development
Truncation of the intracellular carboxyl-terminal tail of Smo, which is necessary for entry into the primary cilium where it controls Gli processing, did not block Smo-activated Gαi signaling [41]. This finding indicated that signals to G proteins and Gli effectors could be separated, suggesting the existence of two independent Smo signaling arms: a canonical route controlling Gli and a noncanonical route involving Gαi, and controlling Shh-induced cellular responses that occur in a Gli-independent manner

Summary

Introduction

The Sonic Hedgehog (Shh) signal transduction network instructs cell fate decisions to drive tissue patterning. Ptch contains a sterol sensing domain that is required for Smo repression [6], suggesting it may target molecules with sterol rings to control Smo activity Consistent with this hypothesis, cholesterol and various oxysterols function as direct Smo agonists [7,8,9]. Ciliary Smo signaling halts Gli processing, allowing for stabilization of Gli and Gli as full-length transcriptional activators responsible for induction of Shh target genes. One such target is Gli, which functions as a feed-forward activator to sustain or amplify target gene expression [22]. We will instead focus on Gli-independent Smo signaling, and discuss the comparatively limited body of work centered on contributions of this noncanonical signaling effector route during embryonic development

Noncanonical Smoothened Signaling

Noncanonical

Axon Fasciculation

Neurotransmitter Selection

Cellular Proliferation

Metabolism

Future Perspectives