Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle.

Marcos Julián Cardozo,Gaia Gestri,Luisa Sánchez-Arrones,África Sandonis,Isabel Guerrero,Cristina Sánchez-Camacho,Paola Bovolenta,Stephen W Wilson

doi:10.1038/ncomms5272

Abstract

Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification. In the absence of Hh signalling, the stalks are not specified, causing cyclopia. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc1). This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Here we show that in the developing zebrafish and chick optic vesicle, in which cdon and ptc1 are expressed with a complementary pattern, Cdon acts as a negative Hh signalling regulator. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion. This Ptc-independent function protects the retinal primordium from Hh activity, defines the stalk/retina boundary and thus the correct proximo-distal patterning of the eye.

Highlights

Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification
In the targets, binding of Hh to a receptor complex containing the seven-pass membrane protein Patched (Ptc), releases Ptc-mediated inhibition of the signal transducer protein Smoothened (Smo), which initiates a cascade of intracellular events that lead to the transcription of Hh target genes[9,10]
Their ectodomains contain five and four immunoglobulin-like domains, respectively, followed by three fibronectin III (FNIII) repeats (1–3), which are involved in Ptc and Hh binding

Summary

Introduction

Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc[1]) This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion This Ptc-independent function protects the retinal primordium from Hh activity, defines the stalk/retina boundary and the correct proximo-distal patterning of the eye. Cdon and Boc are cell surface glycoproteins that belong to a subgroup of the immunoglobulin (Ig) super-family of cell adhesion molecules[14] Their ectodomains contain five and four immunoglobulin-like domains, respectively, followed by three fibronectin III (FNIII) repeats (1–3), which are involved in Ptc and Hh binding. In the absence of Hh signalling, the stalk does not form and Pax6-positive vesicles do not separate, forming a single cyclopic eye[33]

Methods

Conclusion