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J Biol Chem
2013 Jun 07;28823:16655-16670. doi: 10.1074/jbc.M113.451070.
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Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head.
Cases O, Perea-Gomez A, Aguiar DP, Nykjaer A, Amsellem S, Chandellier J, Umbhauer M, Cereghini S, Madsen M, Collignon J, Verroust P, Riou JF, Creuzet SE, Kozyraki R.
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Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development, Cubn is expressed in both embryonic and extra-embryonic tissues, and Cubn gene inactivation results in early embryo lethality most likely due to the impairment of the function of extra-embryonic Cubn. Here, we focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies-conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anteriorhead of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation, and patterning in the developing head, is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs), it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity.
FIGURE 6. XCubn and XFgf8 are together necessary for normal head formation in the frog embryo. A–C′, representative whole-mount mRNA staining of tailbud stage frog embryos unilaterally injected with control (A–C) and MoCubn (A′–C′) morpholinos. A and A′, XFgf8 is expressed in the ANR (arrowhead) and the isthmus (arrow) of the MoCubn-treated embryos. B and B′, reduced XFoxg1 expression domain in the telencephalon (arrowhead) and eye (arrow) after MoCubn injection. C and C′, reduced expression domain of XOtx2 in the developing telencephalon (arrowhead), eye (arrow), and slightly in the midbrain of the MoCubn treated embryo. D, telencephalic and eye (arrowhead) hypoplasia and down-regulation of XFoxg1 mRNA staining in the injected part of the embryo (dotted line, inj). E, increased levels of cleaved caspase-3 in cephalic extracts of MoCubn-treated embryos. F, telencephalic hypoplasia and down-regulation of XFoxg1 in MoFgf8-injected embryos. G and H, low MoFgf8 (0.5 pmol) or MoCubn (0.25 pmol) concentrations do not affect telencephalic development and XFoxg1 expression. I, strong reduction of XFoxg1 in embryos co-injected with MoCubn and MoFgf8 at the same low concentrations. J, reduced or normal expression of XFoxg1 after co-injection of MoCubn and MoFgf8 at the concentrations indicated. The number of embryos analyzed is indicated. Scale bars, A–C, and F–I, 250 μm; D, 75 μm.
Supplemental figure 7. XCubn is expressed during early neurula stages and is required for forebrain and eye morphogenesis. A, B. Cubn is enriched in anterior neural plate extracts of neurula stage 18-20 frog embryos. A. Quantitative RT-PCR analysis shows relatively higher XCubn expression in the anterior neural plate compared to the truncal and caudal parts. Primers to Actin are used to normalize mRNA levels. Relative expression represents the ratio of Cubn/Actin mRNA. In the caudal region this is arbitrary noted as 1; mean of three independent groups of six explants is shown. B. Immunoblot analysis shows higher expression of Cubn in the same region; C. Immunoblot analysis of control embryos and embryos injected at the 2-cell stage with the translation-blocking morpholinos designed here (MoCubn). At all the concentrations tested MoCubns efficiently silences the expression of Cubn; D. Marked eye hypoplasia (arrow) and downregulation of XOtx2 mRNA (blue) in the telencephalic and eye region of the injected part of a late tailbud-stage embryo. Rhodamine-
lysinated dextran is used as lineage tracer of the injection. Black indent line demarcates the dorsal midline, white indent lines demarcate the eye (e) and the telencephalon (t). E. Co- injection of various concentrations of MoCubn and MoFgf8, or MoFgf8 and MoControl, or MoCubn and MoControl, and their effect on the expression of XFoxg1. Summary of two independent experiments indicating the number of embryos analyzed. Scale bars: 250 m.
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