Positive and negative regulation of Shh signalling in vertebrate retinal development

Abstract

Cell-to-cell communication is fundamental for embryo development and subsequent tissue homeostasis. This communication is often mediated by a small number of signaling pathways in which a secreted ligand binds to the surface of a target cell, thereby activating signal transduction. In vertebrate neural development, these signaling mechanisms are repeatedly used to obtain different and context-dependent outcomes. Part of the versatility of these communication mechanisms depends on their finely tuned regulation that controls timing, spatial localization, and duration of the signaling. The existence of secreted antagonists, which prevent ligand-receptor interaction, is an efficient mechanism to regulate some of these pathways. The Hedgehog family of signaling proteins, however, activates a pathway that is controlled largely by the positive or negative activity of membrane-bound proteins such as Cdon, Boc, Gas1, or Megalin/LRP2. In this review, we will use the development of the vertebrate retina, from its early specification to neurogenesis, to discuss whether there is an advantage to the use of such regulators, pointing to unresolved or controversial issues.

Keywords: Cell cell communication; Shh Signalling; development; eye; patterning; regulation; retina.

Figure 1.. Cdon, Boc, and Gas1 act as positive regulators of Shh signaling during optic vesicle formation.

The diagrams represent the interaction of Cdon, Boc, and Gas1 with Ptch and Shh during Shh-mediated patterning of the ventral neural tube in wild-type embryos ( A) or in embryos with genetic inactivation of either Cdon or Gas1 function ( B) or lacking Cdon, Boc, and Gas1 ( C). The three co-receptors interact with Ptch and the complex binds Shh with high affinity. In the presence of Shh, Smo is de-repressed (red crosses) and activates a signal transduction cascade that culminates with Gli-mediated transcription of Shh target genes. The Cdon/Ptch and Boc/Ptch interactions are mediated by the FnIIIa and FnIIIb domains (green) of Cdon and Boc, respectively. Binding of Shh to Cdon or Boc is mediated by the FnIIIc domain (pink). ( B) In the absence of either Cdon or Gas1, Shh is less activated (dotted red crosses), resulting in mild craniofacial defects. ( C) Loss of all three co-receptors prevents pathway activation, resulting in severe HPE, a phenotype that mimics Shh loss of function. Boc, Brother of Cdon; Cdon, cell adhesion molecule-related, downregulated by oncogenes; Gas1, growth arrest protein 1; HPE, holoprosencephaly; Ptch, patched; Shh, sonic hedgehog; Smo, smoothened.

Figure 2.. Cdon, Boc, and Lrp2 antagonize Shh activity during retina development.

( A) Schematic dorsal view of the optic vesicle (left) and enlarged view of the optic stalk/neural retina border (right). The expression domains of Pax2 (blue) and Pax6 (brown) are indicated in the scheme. At the border of these two domains, Cdon binds Shh, serving as a decoy receptor to protect the neural retina from midline-derived Shh activity. Note that the Ptch receptor localizes only in the Pax6-positive neural retina domain. ( B) Schematic frontal view of mature retina (left) and enlarged view of the retinal periphery (right). Contralateral RGCs produce and secrete Shh. Ipsilateral projecting RGCs express the co-receptor Boc that prevents Shh diffusion and thus signal activation. Low Shh signal allows for the specification of ipsilateral program specification in RGCs of the VTC. Lrp2/Megalin instead limits Shh proliferative activity by endocytic clearance of Shh at the CMZ. Boc, Brother of Cdon; Cdon, cell adhesion molecule-related, downregulated by oncogenes; CMZ, ciliary marginal zone; Hyp, hypothalamus; Lrp2, low-density lipoprotein receptor-related protein 2; NR, neural retina; OS, optic stalk; Pax2, paired box protein Pax-2; Pax6, paired box protein Pax-6; Ptch, patched; RGC, retinal ganglion cell; Shh, sonic hedgehog; VTC, ventrotemporal crescent.