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BACKGROUND: The mesoderm of the amphibian embryo is formed through an inductive interaction in which vegetal cells of the blastula-staged embryo act on overlying equatorial cells. Candidate mesoderm-inducing factors include members of the transforming growth factor type beta family such as Vg1, activin B, the nodal-related proteins and derrière.
METHODOLOGY AND PRINCIPLE FINDINGS: Microarray analysis reveals different functions for activin B and the nodal-related proteins during early Xenopus development. Inhibition of nodal-related protein function causes the down-regulation of regionally expressed genes such as chordin, dickkopf and XSox17alpha/beta, while genes that are mis-regulated in the absence of activin B tend to be more widely expressed and, interestingly, include several that are involved in cell cycle regulation. Consistent with the latter observation, cells of the involuting dorsal axial mesoderm, which normally undergo cell cycle arrest, continue to proliferate when the function of activin B is inhibited.
CONCLUSIONS/SIGNIFICANCE: These observations reveal distinct functions for these two classes of the TGF-beta family during early Xenopus development, and in doing so identify a new role for activin B during gastrulation.
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Figure 1. Inhibition of activin B and nodal-related protein function causes distinct phenotypes and results in the differential regulation of different classes of gene.(A,D) Control embryos (here injected with water; those injected with mMO1 look identical) at stage 11 (A) and 26 (D). (B,E) Embryos injected with MO3, and which therefore lack activin B activity. (B) Stage 11; (E) stage 21. Note the delay in gastrulation and the failure to form a proper axis. (C,F) Embryos injected with Cerberus-short RNA, and which therefore lack nodal-related activity. Note the failure to involute and the formation of a radially symmetrical structure. (G,H). Correlation between microarray and PCR results.
Figure 2. Expression patterns of genes regulated by activin and nodal-related proteins.(A,B) Expression pattern of Chordin, a gene that is mis-regulated following inhibition of Xnr signalling. Note that Chordin transcripts are restricted to the dorsal marginal zone. (C–F) Expression pattern of DNMT1, a gene that is mis-regulated following inhibition of activin signalling. (C) and (D) show embryos hybridised using a sense probe; (E) and (F) show embryos hybridised using an antisense probe. Note that DNMT1 is expressed ubiquitously.
Figure 3. Inhibition of activin B function prevents dorsal axial mesoderm from exiting the cell cycle.(A) Diagram illustrating from which part of the embryo sections in (B–E) are derived. (B,C) Composite images of 10 serial sagittal sections of representative embryos stained with an antibody recognising phosphorylated histone H3 as whole mounts and then sectioned at 12 µm. (B) Control embryo injected with mMO1. Note absence of mitotic cells in involuting mesoderm. (C) Embryo injected with specific antisense oligonucleotide MO3. Involution is perturbed and mitotic cells are visible in dorsal tissue. (D,E) Frozen sections of embryos stained with an antibody recognising phosphorylated histone H3. (D) Control embryo injected with mMO1. Note absence of mitotic cells in involuting mesoderm. (E) Embryo injected with specific antisense oligonucleotide MO3. Involution is perturbed and mitotic cells are visible in dorsal tissue.
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