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.
The related gene lnx2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. We found that Lnx2a, in redundant function with Lnx2b, is required for early pancreas differentiation in zebrafish. Without Lnx2 function, differentiation of exocrine cell types is inhibited whereas endocrine cells develop normally. We have shown that Lnx2 destabilizes Numb in pancreas cells, which allows function of Notch. Loss of Lnx2 function leads to overexpression of Numb and reduction of Notch function, which affects the differentiation of pancreatic cell types. Thus Lnx2, through regulation of Numb and Notch, modulates the balance of cell types that differentiate in the early zebrafish pancreas.
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 is specified. Overexpression of Kctd15 strongly inhibits NC specification, suggesting that Kctd15 is involved in regulating NC formation. We showed that Kctd15 inhibits the function of the transcription factor AP-2, a known key regulator of NC formation. Kctd15 binds to the AP-2 activation domain, and this binding is required for its inhibitory action. The study of the role of Kctd15 in development is ongoing in the laboratory.