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Our group studies the frog Xenopus laevis and the zebrafish Danio rerio to obtain insights into mechanisms of vertebrate development. We use molecular and genetic screens to identify genes that regulate development, with an emphasis on signaling pathways, transcriptional regulation and the regulation of protein stability and function. Recent research is summarized below.
We have shown that the E3 ubiquitin ligase Lnx-2b (previously known as Lnx-like) has a role in regulating axis specification in the early zebrafish embryo. Lnx-2b regulates organizer formation by limiting the stability of the homeodomain protein Dharma/Bozozok/Nieuwkoid, thereby assuring the proper balance between organizer and ventral domains in the early gastrula embryo.
Lnx-2b and its interacting partner E4f1 have a role in the regulation of the formation of the caudal region in the zebrafish embryo. The Wnt target gene cdx4 controls development of caudal tissues and is essential for hematopoiesis. We found that regulation of cdx4 by Wnt signaling is stimulated by the transcription factor E4f1 while this effect is opposed by Lnx-2b. In the regulation of cdx4, the Wnt effector Tcf3 acts as a repressor while Wnt signaling leads to de-repression. E4f1 acts by dissociating the Tcf3 repressor complex and thus cooperates with Wnt signaling in caudal body formation. We suggest that the action of E4f1 assures robustness of the graded expression of cdx4 in the caudal body region.
Our laboratory has a long-standing interest in the formation of the neural crest (NC), a group of cells with stem cell properties that arise at the dorsal neural tube, migrate to many locations in the embryos and give rise to multiple differentiated derivatives. We study the role of the BTB domain-containing protein Kctd15 in regulating the NC domain. Kctd15 is first expressed at the neural plate border where the NC and the pre-placodal domains are specified. Overexpression of Kctd15 strongly inhibits NC specification, whereas knock-down of Kcdt15 enhances the expression of NC marker genes. At the same time anterior placodal domains are enlarged by Kctd15 overexpression. On the basis of these observations we propose that Kctd15 is involved in delineating the separate pre-placodal and NC domains at the neural plate border. Kctd15 function in the embryo continues to be actively pursued in the laboratory.