Bell E et al. (2003), Cell fate specification and competence by Coco,...

XB-ART-5759

Development 2003 Apr 01;1307:1381-9. doi: 10.1242/dev.00344.

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Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor.

Bell E , Muñoz-Sanjuán I , Altmann CR , Vonica A , Brivanlou AH .

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Patterning of the pre-gastrula embryo and subsequent neural induction post-gastrulation are very complex and intricate processes of which little, until recently, has been understood. The earliest decision in neural development, the choice between epidermal or neural fates, is regulated by bone morphogenetic protein (BMP) signaling within the ectoderm. Inhibition of BMP signaling is sufficient for neural induction. Many secreted BMP inhibitors are expressed exclusively within the organizer of the Xenopus gastrula embryo and therefore are predicted to act as bona fide endogenous neural inducers. Other cell-autonomous inhibitors of the BMP pathway are more widely expressed, such as the inhibitory Smads, Smad6 and Smad7. In this report we describe the biological and biochemical characterization of 51-B6, a novel member of Cerberus/Dan family of secreted BMP inhibitors, which we identified in a screen for Smad7-induced genes. This gene is expressed maternally in an animal to vegetal gradient, and its expression levels decline rapidly following gastrulation. In contrast to known BMP inhibitors, 51-B6 is broadly expressed in the ectoderm until the end of gastrulation. The timing, pattern of expression, and activities of this gene makes it unique when compared to other BMP/TGFbeta/Wnt secreted inhibitors which are expressed only zygotically and maintained post-gastrulation. We propose that a function of 51-B6 is to block BMP and TGFbeta signals in the ectoderm in order to regulate cell fate specification and competence prior to the onset of neural induction. In addition, we demonstrate that 51-B6 can act as a neural inducer and induce ectopic head-like structures in neurula staged embryos. Because of this embryological activity, we have renamed this clone Coco, after the Spanish word meaning head.

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Species referenced: Xenopus
Genes referenced: bmp4 cer1 dand5 emx1 emx1l en2 fgf8 gdf1 gsc hoxb9 hoxc9-like nkx2-5 odc1 otx2 rax smad6.2 smad7 tbxt tgfb1 vegt

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Fig. 2. Expression pattern of Coco mRNA during Xenopus development. (A) Whole-mount in situ hybridisation of Coco, Bmp4 and VegT mRNA in the egg. Expression of Coco was also compared to Vg1 by RT-PCR. (B) Coco is expressed strongly in the animal pole at the 2-cell, 8-cell stages and at stage 8. (C) Coco is strongly expressed maternally and then is downregulated at the post-gastrula/pre-neurula stages. In contrast Cerberus is first expressed at stage 9 and then downregulated after the onset of neurulation. (D,E) At gastrula stage Coco is detected at high levels in the ectoderm and marginal zones by (D) whole-mount in situ hybridisation and (E) as seen by RT-PCR at much lower levels in the vegetal pole. ODC was used as a loading control for the RT-PCR. * indicates the organizer.

Fig. 3. Phenotypes resulting from Coco overexpression in Xenopus embryos. Analysis of injected embryos at gastrula (A-D), neurula (H) and early tadpole stages (E-G,I-N). In A-D and H-N, the top panels are uninjected embryos, the lower panels are embryos injected with 1 ng Coco vegetally in 1 cell at the 2-cell stage (A-D) or ventrally in one cell at the 4-cell stage (G-N). (A) Xbra/brachyury (a marker of mesoderm); (B) Fgf8, also a mesoderm marker, (C) Otx2, (the organizer and anterior ectoderm); (D) gsc (organizer); (H) rx, (forebrain); (I) Emx1 (dorsal telencephalon); (J) Otx2, forebrain and midbrain; (K) En2 (midbrain/hindbrain boundary); (L) Hoxb9 (spinal cord); (M) Nkx2.5 (heart) (N) 12-101 Ab (muscle). (E-G) Phenotypes resulting from (E) no injection (control embryo); (F) dorsal animal injection at the 2-cell stage; (G) injection in one ventral vegetal cell at the 4-cell stage. *indicates the extra head structures. A,B,D are vegetal views; C, lateral with animal pole to the top; E-G,I-K, lateral views; H,L,N dorsal views; M, ventral view. In E-N, anterior is to the right.