FGF Receptor Modulator Implicated in Brain Development

Science's STKE  28 Feb 2006:
Vol. 2006, Issue 324, pp. tw78
DOI: 10.1126/stke.3242006tw78

During brain development, instructive signals between the midbrain and the isthmus (the boundary region between the midbrain and hindbrain) control the development of the future tectum and cerebellum. One critical signal is mediated by fibroblast growth factor 8 (FGF8). Hirate and Okamoto report studies of this developmental regulatory system and identify a previously unrecognized regulator of FGF signaling. The authors previously identified a zebrafish gene they named canopy1 in a screen for genes expressed at the isthmus in response to signaling between the midbrain and the isthmus. Their new work showed that implantation of FGF8b-soaked beads in the midbrain of zebrafish embryos increased expression of canopy1. Experiments in which expression of Canopy1 protein was blocked with antisense morpholino oligonucleotides showed that Canopy1 was essential for normal development of the tectum and cerebellum. Such inhibition of Canopy1 function also inhibited FGF8b-induced expression of a target gene, eng2a. The defect in FGF signaling appeared to be at the level of the receptor, because an artificially constructed FGF receptor activated by a dimerizing agent could still activate expression of eng2a in the absence of Canopy1. Canopy1 contains a sequence similar to ER (endoplasmic reticulum) retention signals, and, in transfected HeLa cells, this domain appeared to be required for retention of the protein in the ER. The human ortholog of Canopy1 was also localized to the ER in HeLa cells. Immunoprecipitation studies on extracts of cells transfected with a tagged Canopy1 protein along with full-length or fragmented FGF receptor protein suggested that Canopy1 may interact with the extracellular domain of the FGF receptor. The authors note that Canopy1 has structural similarity to saposins, proteins that bind sphingolipids, and speculate that Canopy1 could influence association of the receptor with lipid rafts.

Y. Hirate, H. Okamoto, Canopy1, a novel regulator of FGF signaling around the midbrain-hindbrain boundary in zebrafish. Curr. Biol. 16, 421-427 (2006). [PubMed]