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Research Areas

Intersection of transcriptional and signalling activity in development

Our genetic and embryological studies showed that for the head to develop correctly, stringent control of WNT signalling is required, synergistically interacting with transcriptional activity regulated by the Lhx1 gene. Head abnormalities also occur in Saethre-Chotzen syndrome, caused by errors in the TWIST1 gene. We used mouse models to show that loss of Twist1 affects different components of the craniofacial skeleton and the muscles of the face, eyes and jaws. Losing Twist1 function in the limb causes malformations of the fingers and the bones of wrist and forearm due to changes in signalling activity.
 

Molecular control of gut development

We studied the role of the Rbm47 gene, which encodes an RNA binding protein expressed in the cells lining the gut. Reduced function of this gene in genetic mouse models leads to abnormal differentiation of the gut lining and disrupts its maturation. We also identified a CDC42-related Rho GTPase that is active in the endoderm, the embryonic tissue that forms organs including the liver, pancreas and thyroid. By lowering the activity of this gene, we showed that it is required for proper cellular organization within the endoderm. Reduced gene function results in an abnormal organization of the epithelium, which appears to be critical for endoderm cells to respond properly to signals from surrounding tissues.
 

Developmental function of Importin, an importer of protein into the nucleus

Importin 13 is a member of a large importin ß superfamily of proteins that mediate the transport of proteins into the nucleus. Importin 13 (Imp13) function is closely linked to disease states such as X-linked mental retardation and childhood asthma and is implicated in development of the foetal lung, testis, brain and cornea. In contrast to other Importins, full length (“L-”) Imp13 appears to have dual specific nuclear import and export roles; but it is not clear how it can mediate transport bi-directionally, what specific import or export sequences it recognises, and how this relates to the function of a novel testis-specific variant (“tImp13”). Our analysis of Imp13 mutant mice indicates that Imp13 is essential for early development, and nuclear transport kinetic measurements in living cells imply that tImp13 can inhibit nuclear import mediated by L-Imp13. We hypothesise that Imp13 targets a number of specific cargoes into/out of the nucleus that are critical to mammalian development, and that inhibition of nuclear import by the tImp13 variant is an important counteracting mechanism. Our work, which is carried out in collaboration with Professor David Jans’ team at Monash University, aims to elucidate L-Imp13/tImp13 function using a range of molecular cell biology, biochemistry and genetic approaches.
 

Mouse embryo-derived stem cells for studying germ layer differentiation

We have derived a new type of stem cell from mouse embryos poised to undergo germ layer formation. These cell types can renew themselves in culture and can differentiate into cell types of multiple lineages. Derived from mouse embryos at different developmental stages, they display unique patterns of gene activity and lineage potency. We are currently optimising the method to direct the differentiation of these cells, and induced pluripotent cells generated by reprogramming fully differentiated cells, into gut cells (specifically liver and pancreas cells). The goal is to test, in collaboration with the Gene Therapy Unit, the principle and feasibility of combining cell-based and gene therapy to treat inborn errors of metabolism.