Mutation in the Ciliary Protein C2CD3 Reveals Organ-Specific Mechanisms of Hedgehog Signal Transduction in Avian Embryos.

Evan C Brooks,Nandor Nagy,Anne H Carroll,Samantha A Brugmann,Christian Louis Bonatto Paese,Jaime N Struve

doi:10.3390/jdb9020012

Abstract

Primary cilia are ubiquitous microtubule-based organelles that serve as signaling hubs for numerous developmental pathways, most notably the Hedgehog (Hh) pathway. Defects in the structure or function of primary cilia result in a class of diseases called ciliopathies. It is well known that primary cilia participate in transducing a Hh signal, and as such ciliopathies frequently present with phenotypes indicative of aberrant Hh function. Interestingly, the exact mechanisms of cilia-dependent Hh signaling transduction are unclear as some ciliopathic animal models simultaneously present with gain-of-Hh phenotypes in one organ system and loss-of-Hh phenotypes in another. To better understand how Hh signaling is perturbed across different tissues in ciliopathic conditions, we examined four distinct Hh-dependent signaling centers in the naturally occurring avian ciliopathic mutant talpid2 (ta2). In addition to the well-known and previously reported limb and craniofacial malformations, we observed dorsal-ventral patterning defects in the neural tube, and a shortened gastrointestinal tract. Molecular analyses for elements of the Hh pathway revealed that the loss of cilia impact transduction of an Hh signal in a tissue-specific manner at variable levels of the pathway. These studies will provide increased knowledge into how impaired ciliogenesis differentially regulates Hh signaling across tissues and will provide potential avenues for future targeted therapeutic treatments.

Highlights

Primary cilia are ubiquitous microtubule-based organelles that sense the molecular and mechanical environment of the cell [1]
In the absence of an Hh ligand, Smo is repressed by Ptch1 and the glioma-associated oncogene (Gli) transcription factors are proteolytically processed into their truncated repressor isoforms (GliR) that will repress target gene expression
Previous studies that investigated Hh signaling in the ta2 limb focused on stages after morphological differences were first visible [51,52,53]

Summary

Introduction

Primary cilia are ubiquitous microtubule-based organelles that sense the molecular and mechanical environment of the cell [1]. When there are disruptions in the structure or function of primary cilia, a growing class of heterogenous disorders called ciliopathies arise. Hh-Ptch binding relieves the Ptch1-mediated inhibition of the Hh pathway transducer Smoothened (Smo) [9]. Smo transduces the Hh signal through the glioma-associated oncogene (Gli) family of transcription factors (Gli, Gli, Gli). Hh pathway activation promotes the processing of the Gli transcription factors into their full-length activator isoforms (GliA) that will activate target gene expression [21]. In the absence of an Hh ligand, Smo is repressed by Ptch and the Gli transcription factors are proteolytically processed into their truncated repressor isoforms (GliR) that will repress target gene expression. Post-translational processing of Gli2/3 into their GliA and GliR isoforms occurs at the primary cilium and disrupted ciliogenesis impairs the production of GliA and GliR isoforms [1,22,23]

Methods

Results

Conclusion