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Patterning of the central nervous system is regulated by a signaling center located at the midbrain-hindbrain boundary (MHB), or isthmusorganizer. Fibroblast growth factors secreted from the MHB are required and sufficient to direct the ordered growth and regionalization of the midbrain and anteriorhindbrain. In an unbiased secretion cloning screen of Xenopus gastrula embryos we identified a novel gene, which we designated as Isthmin (xIsm) due to its prominent expression at the MHB. xIsm encodes a secreted protein of 449 amino acids containing one copy of the thrombospondin type 1 repeat (TSR). We also found orthologous Isthmin genes in human (hIsm) and mouse (mIsm), as well as a gene encoding an Isthmin-like human unknown protein (hIsm-l). The conservation of a unique carboxy-terminal region between hIsm and hIsm-l suggests that Isthmin is the founding member of a new family of secreted proteins. xIsm was strongly expressed maternally in the Xenopus egg and showed zygotic expression in the ventralblastopore lip, notochord, and MHB. Additional expression domains were detected in neural crest, ear vesicle, and developing blood islands. Interestingly, xIsm was co-expressed with Fibroblast growth factor-8 (xFgf-8) at multiple sites including the MHB, indicating that these two genes are part of a synexpression group which also includes sprouty and sef homologs.
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Fig. 2. Expression of Xenopus Isthmin by whole-mount in situ hybridization. Embryos are shown in animal (A), vegetal (B–D), dorsal (E,G), anterior (F,H) or lateral (I–K) view.
(A) Four-cell stage embryo; note the high level of maternal transcripts.
(B–D) Embryos at gastrula stage showing distinct expression in the ventralblastopore lip (vbl), and the anterior end of the notochord (n).
(E,F) Early neurulae showing strong expression throughout the notochord, the posterior paraxial mesoderm (pa), cranial neural crest (nc) and anterior edge of the neural plate (anp). The arrowheads mark expression at the prospective midbrain–hindbrain boundary.
(G) Late neurula with an additional expression domain in the posterior neural fold (nf).
(H,I) Early tailbud stage; note strong expression at the midbrain–hindbrain boundary (arrowheads).
(J,K) Tailbud stage; xIsm expression is apparent in the branchial arches (ba), ear placode (e) and ventralmesoderm (vm).
Fig. 3. Comparison of xIsm and xFgf-8 expression. (A,D) Stage 10 embryos in vegetal view; note that xIsm and xFgf-8 expression overlap in the ventrolateral blastopore lip (vbl). (B,E) Stage 17 embryos in dorso-vegetal view showing expression of xIsm and xFgf-8 in the anterior notochord (n). (C,F) Stage 20 embryos in anterior view; note overlapping expression of xIsm and xFgf-8 in cranial neural crest (nc), anterior edge of neural plate (anp), and midbrain–hindbrain border (arrowheads). (G–I) Stage 30 embryos in lateral view. (G) Whole-mount in situ hybridization depicting xIsm expression in the branchial arches (ba), diencephalon (di), ear placode (e), and isthmus (arrowhead). (H) xFgf-8 expression at the same stage. (I) Double in situ hybridization of xIsm and xFgf-8; note the overlap of expression in branchial arches, diencephalon and isthmus (arrowhead), as well as the complementary expression in the ear placode.
fgf8 (fibroblast growth factor 8) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 10, vegetal (blastoporal) view.
