91猎奇

I am interested in the establishment of cell fate and spatial pattern in vertebrate embryos. Embryonic cells must integrate information from a diverse array of extracellular signals in order to make developmental decisions. For example, ectoderm cells choose between neural and epidermal fates in response to several growth factors, including Bone Morphogenetic Protein-4 (BMP4), which induces epidermis, as well as Fibroblast Growth Factors (FGFs) and Insulin-like Growth Factor (IGF), which have been implicated in the specification of neural fate. Studies in my lab investigate signaling pathway interactions and transcriptional regulation in the establishment of ectodermal fate and anteroposterior pattern in Xenopus embryos.

Current Projects

Interactions Between FGF and BMP Signaling Pathways

Our earlier studies showed that the erk-MAPK pathway, a key effector of FGF signaling, is essential for the establishment of neural fate. We have identified antagonistic interactions between FGF and BMP4 signaling pathways which contribute to the regulation of neural fate. In each instance, we are investigating the mechanism of the interactions and their developmental significance. For example, BMP4 inhibits expression of FGF receptors 1 and 4; this inhibition restricts the spatial range of FGF signaling, but not the duration of competence to respond to FGF. Our ongoing studies investigate the role of erk-MAPK in the regulation of BMP4/ Smad1-dependent transcription, as well as the mechanisms underlying the inhibition of erk-MAPK by the BMP4 effector TAK1. One key hypothesis is that antagonistic interactions between these pathways can regulate boundary formation between developmentally distinct regions. FGFs and BMPs act antagonistically to regulate many developmental processes, including limb outgrowth, remodeling of the heart by apoptosis, positioning of teeth and feathers, and blood formation, among others. Thus, our findings elucidate a conserved regulatory circuitry that may underlie many processes in vertebrate development.

Role of Ashwin in the Establishment of Anteroposterior Pattern

We previously identified ashwin, a novel highly conserved gene, in a differential display screen for genes expressed at initial stages of neural specification. Ashwin is a transcriptional repressor, and overexpression of ashwin leads to a puzzling combination of phenotypes, including both double-axis, or twinned, embryos, and embryos with anterior truncations. Our working hypothesis is that both phenotypes result from localized inhibition of the anterior organizer, although ashwin apparently has multiple targets at different developmental stages. Loss-of-function studies suggest that ashwin regulates cell survival, and it may also be required for the establishment of posterior pattern. We are currently investigating the mechanisms of ashwin action and its role in early development.