The zebrafish reveals a role for the tumour suppressor, HACE1, in cardiac development

HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is an enzyme that is responsible for helping cells properly break down proteins. Its loss of function was originally discovered in a case of pediatric kidney cancer, known as Wilms' tumour. The zebrafish is an excellent model in which to study human diseases. They are vertebrates like us, and they have high similarity to our development and cell biology. Moreover, their embryos are transparent, enabling easy observation of early development over time. When HACE1 function is suppressed in zebrafish, they have a high frequency of heart deformities. This project aims to determine the mechanism through which HACE1 operates to cause these defects. I will first focus on the one known protein that HACE1 helps to break down, Rac1. There are likely other targets of HACE1 that may be linked to its function in the heart, and a second aim of my project is to identify these proteins. First, I will eliminate HACE1 in a population of zebrafish by causing a mutation in the gene that produces this enzyme. I will confirm heart defects in these fish, and determine if their Rac1 levels are higher. If so, I will suppress Rac1 in these fish to see if it improves their heart deformities. I will also look at the effects of HACE1 loss on the expression of other genes in zebrafish hearts. This will reveal new pathways affected by the HACE1 enzyme, from which I will identify candidates that are most likely linked to heart development. These candidates will be examined in zebrafish embryos to see if they affect development, and in cultured human cells to look at cell-level effects. This study promises to reveal, for the first time, a role for HACE1 in normal heart development and whether loss of HACE1 could serve as a marker for tumour development.