Birth defects are a major cause of infant morbidity and mortality. My research focuses on understanding the genetic and molecular causes of these anomalies. In particular, I am using frog and cell culture models to investigate a number of congenital cardiac, craniofacial and ribosome diseases. My work currently focuses on two main themes;

1 – Rapgef5 regulates the nuclear transport of β-catenin

Canonical Wnt signaling coordinates many critical aspects of Untitled-3embryonic development, while dysregulated Wnt signaling contributes to numerous common diseases, including congenital malformations and cancer. The nuclear localization of β-catenin is fundamental in pathway activation. However, despite intensive investigation, the mechanisms regulating β-catenin nuclear transport remain undefined. β-catenin nuclear transport is energy (GTP) dependent but β-catenin lacks a classic “NLS” nuclearlocalization signal and does not require the karyopherin/Ran GTPase transport system. We have discovered a nuclear localized guanine nucleotide exchange factor (GEF) that is an unexpected regulator of β-catenin nuclear transport. Identified in a human patient, we have shown that Rapgef5 alters development of the head and heart via Wnt signaling and the nuclear localization of β-catenin, rather than β-catenin degradation. Together, our results define a novel GTPase based system that facilitates nuclear transport of β-catenin, and suggest new targets for the modulation of Wnt signaling in disease.

I am now to building on this preliminary work to fully explore the cell biology, developmental requirements and disease significance of this discovery.

2 – Investigating the etiology of ribosomopathies

Ribosomes are essential for all cells to produce the proteins needed for their homeostasis. Therefore, a priori, defects in the synthesis of ribosomes should lead to cell death; yet mutations affecting ribosome production have now been identified in several human congenital disorders (ribosomopathies) and in animal models. Despite all arising from abnormalities in the ubiquitous process of ribosome biogenesis, these diseases exhibit a strikingly diverse set of clinical phenotypes. This tissue proclivity is highly unexpected, and the mechanisms that might explain these phenotypes remain mostly unexplored. Along with colleagues at the Yale School of Medicine and King’s College London , I am working to understand the molecular origins of these diseases.