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Evidence is presented for a new pathway participating in anterior neural development. It was found that IGF binding protein 5 (IGFBP-5), as well as three IGFs expressed in early embryos, promoted anterior development by increasing the head region at the expense of the trunk in mRNA-injected Xenopus embryos. A secreted dominant-negative type I IGF receptor (DN-IGFR) had the opposite effect. IGF mRNAs led to the induction of ectopic eyes and ectopic head-like structures containing braintissue. In ectodermal explants, IGF signals induced anterior neural markers in the absence of mesoderm formation and DN-IGFR inhibited neural induction by the BMP antagonist Chordin. Thus, active IGF signals appear to be both required and sufficient for anterior neural induction in Xenopus.
Figure 1. IGFBP-5 Is Expressed Dorsally and Has Anteriorizing Activity(A) SDS-PAGE of conditioned medium from 293Tcells labeled with 35S-cysteine and -methionine and transfected with GFP (control) or xIGFBP-5 cDNA. Protein bands at 38 kDa and 18 kDa correspond to xIGFBP-5 full-length protein and proteolytic cleavage products, respectively.(B) Schematic structure of IGFBP-5. SP, N-terminal signal peptide; IB, IGF binding domain; TY, thyroglobulin type I repeat. The GCGCCXXC sequence critical for IGF binding (Kalus et al., 1998) is indicated.(C) Sequence alignment of Xenopus and human IGFBP-5 proteins. The arrowhead indicates the predicted signal peptide cleavage site and the red and blue bars indicate the IG and TY, respectively.(D–H) Whole-mount in situ hybridization of xIGFBP-5 transcripts.(D) Animal view at the 4-cell stage.(E) Dorsal view at neural plate stage showing xIGFBP-5 expression in the dorsal midline.(F) Transverse section of the embryo at neural plate stage; expression is seen in floor plate (fp), notochord (nc), and dorsal endoderm (de).(G) Lateral view of tailbudtadpole.(H) Transverse section of tailbudembryo showing xIGFBP-5 expression in dorsal fin (df), floor plate (fp), and hypochord (hy).(I) Uninjected control.(J) Embryo radially injected with a total of 400 pg xIGFBP-5 mRNA into the animal pole of embryos at the 4- to 8-cell stage (93%, n = 106). Note the enlargement of the cement gland.(K) Uninjected embryo stained for Otx-2 at neurula stage.(L) Sibling injected dorsally with 100 pg of IGFBP-5 mRNA.(M) Ectopic expression of Otx-2 after ventral injection of 100 pg IGFBP-5 mRNA
Figure 3. IGF Signaling and the Head/Trunk Boundary(A) Uninjected 3 day tadpole in lateral view.(B) Embryo injected with 500 pg of DN-IGFR mRNA per animal blastomere at the 4- to 8-cell stage showing reduction of cement gland and eye structures (92%, n = 48).(C–H) The domains of expression of Otx-2 (head), XAG-1 (cement gland), and Rx2a (eye) markers are reduced by DN-IGFR mRNA.(I–N) Dorsal views of neurula stage embryos injected into one blastomere at the 4-cell stage with nuclear lacZ mRNA (note red nuclei). In situ hybridization was performed at neurula stage with probes for Six-3 (I–K) or a combination of Otx-2 and the trunk marker HoxD1 (L–N). IGF-2 (400 pg) shifts the head/trunk border caudally (n = 25) and DN-IGFR mRNA (500 pg) displaces it anteriorly (n = 15). IGF-2 and DN-IGFR mRNA injections do not significantly change the number of nuclear LacZ-labeled nuclei
