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The first total synthesis of Aplidiopsamine A, a rare 3H-pyrrolo[2,3-c]quinoline alkaloid from the Aplidiopsis confluata, has been achieved following the proposed biosynthesis. This biomimetic synthesis requires only five steps and proceeds in 20.8% overall yield. Biological evaluation across large panels of discrete molecular targets identified that Aplidiopsamine A is a highly selective PDE4 inhibitor, a target for numerous CNS disorders.
Induction and patterning of the mesodermal germ layer is a key early step of vertebrate embryogenesis. We report that FoxD3 function in the Xenopus gastrula is essential for dorsal mesodermal development and for Nodal expression in the Spemann organizer. In embryos and explants, FoxD3 induced mesodermal genes, convergent extension movements and differentiation of axial tissues. Engrailed-FoxD3, but not VP16-FoxD3, was identical to native FoxD3 in mesoderm-inducing activity, indicating that FoxD3 functions as a transcriptional repressor to induce mesoderm. Antagonism of FoxD3 with VP16-FoxD3 or morpholino-knockdown of FoxD3 protein resulted in a complete block to axis formation, a loss of mesodermal gene expression, and an absence of axial mesoderm, indicating that transcriptional repression by FoxD3 is required for mesodermal development. FoxD3 induced mesoderm in a non-cell-autonomous manner, indicating a role for secreted inducing factors in the response to FoxD3. Consistent with this mechanism, FoxD3 was necessary and sufficient for the expression of multiple Nodal-related genes, and inhibitors of Nodal signaling blocked mesoderm induction by FoxD3. Therefore, FoxD3 is required for Nodal expression in the Spemann organizer and this function is essential for dorsal mesoderm formation.
Chordates, including vertebrates, evolved within a group of animals called the deuterostomes. All holoblastic deuterostomes gastrulate at the vegetal pole and the blastopore becomes the anus, while a mouth is formed at the anterior or to the oral side. Nodal is a member of the TGF-beta superfamily of signaling molecules that are important in signaling between cells during many embryonic processes in vertebrate embryos. Nodal has also been found in other invertebrate deuterostomes, such as ascidians and sea urchins, but, so far, is missing in protostomes. Nodal has been shown to be particularly important in determining left-right asymmetries in vertebrate embryos, but less information is available for its developmental role in the invertebrate deuterostomes. We review gastrulation in the deuterostomes, then examine nodal expression early during mesoderm formation and later during the establishment of asymmetries in both vertebrates and invertebrates. Nodal is expressed asymmetrically on the left side in chordates and on the presumptive oral side of the embryo in echinoid echinoderms. The expression of nodal is in different germ layers in embryos of different phyla. Expression is in the ectoderm in most of the invertebrate deuterostomes, and in the mesoderm in vertebrates. We summarize the work that has been published to date, especially nodal expression in the invertebrate deuterostomes, and suggest future experiments to better understand the evolution of nodal signaling and deuterostome gastrulation.
(c) 2005 Wiley-Liss, Inc.