One of the most important and defining processes during development is the pattern formation of the various compartments in embryos. In an effort to discover the participants involved in regulating compartment size, we identified, in Danio rerio (zebrafish) embryos, the ankyrin repeat and SOCS box-containing protein 11 (d-asb11) gene. We first showed that d-Asb11 is a key mediator of Delta-Notch Signaling, acting at the level of DeltaA ubiquitylation, important in fine-tuning the lateral inhibition gradients between DeltaA and Notch. We, then, isolated a zebrafish having a germline deletion of the d-Asb11 cullin box subdomain and showed that this deletion resulted in loss of d-Asb11 activity. As a consequence, the animals were defective for Notch signaling and proper cell fate specification within the neurogenic regions of zebrafish embryos. We also provided evidence that d-Asb11 is important in maintaining myogenic proliferation in the stem cell compartment of zebrafish embryos and muscle regenerative responses in adult animals. This finding is supported by the highly specific d-Asb11 expression found in proliferating satellite cells in zebrafish muscle. In addition, we have applied immunoaffinity chromatograpy followed by tandem mass spectrometry to identify human ASB11 interacting proteins. The data confirmed the role of ASB11 as a substrate-recognition that targets proteins for ubiquitylation and proteasomal degradation via the canonical ECS ubiquitin ligase complex. Altogether our results provide important new insight on the action and function of ASB11 in regulating progenitor compartment expansion, possibly by controlling protein levels in the cells.
|Qualification||Doctor of Philosophy|
|Award date||25 Mar 2011|
|Publication status||Published - 2011|