Gene function and RNA processing in gut endoderm development

Summary

This project aims to unravel the impact of RNA processing on the function the targets of a RNA binding protein in the development of the embryonic gut and the associated organs.

Supervisor(s)

Dr Nicolas Fossat, Professor Patrick Tam

Research Location

Westmead - Childrens Medical Research Institute

Program Type

Masters/PHD

Synopsis

This project addresses a fundamental issue of embryonic development at the start of life: the molecular activity controlling the formation of major body parts of the embryo. The epithelium of the primitive gut is formed from definitive endoderm and the muscle and connective tissues are mesoderm-derived. The foregut forms the liver, pancreas, the epithelium of the digestive tract and lungs, the thymus, thyroid and parathyroid glands. The molecular basis for the formation, organization and differentiation of these organs is not well understood, and this project is aimed at contributing to our knowledge of this process. As a first step towards this, we compared the genes expressed in the foregut endoderm of mouse embryos with tissues that do not contain endoderm using microarrays. From this analysis we identified a set of genes that are predominantly expressed in the endoderm and which do not, as yet, have any known function in early development. We are now using a variety of approaches to study the functions of some of these genes during development of the endoderm and its derivative organs. In this project, the effects of reduced or loss of gene function (by knockdown, gene-targeting or gene-trap) and gain of gene function (by electroporation, transfection and transgenesis) will be tested in mouse embryos, embryonic stem cells and other appropriate cell models such as mini-gut organoids.

In particular, we are investigating the function of the RNA binding protein RBM47. We demonstrated that RBM47 is involved in Cytidine to Uridine RNA editing, an unusual post-transcriptional modification, the splicing of transcripts and inlfuencing the stability of RNA. Transgenic mice that lack or overexpress Rbm47 display developmental defects. Current projects aim to identify the ensemble of targets and partners of RBM47 and understand its role in RNA processing for the formation and the physiology of endoderm-derived organs.

Additional Information

Children's Medical Research Institute (CMRI) is an award-winning state-of-the-art medical research facility, with over 100 full-time scientists dedicated to researching the genes and proteins important for health and human development. The CMRI is supported in part by its key fundraiser Jeans for Genes®. Our scientists are internationally recognised research leaders and foster excellence in postgraduate training. CMRI graduates are highly sought after nationally and internationally.

CMRI is located at Westmead, a major hub for research and medicine in NSW, and is affiliated with the University of Sydney. Easy to access by public transport.

We are looking for top quality students who can prove a dedicated interest and enthusiasm for scientific research.

Candidates may apply for a CMRI PhD Research Award, which exceeds the Australian Postgraduate Awards and NHMRC scholarships in value. Visit the CMRI website for more details.

Methodologies:
Genome analysis (RNA-seq, ChIP-Seq, iCLIP-Seq, single-cell transcriptome), protein analysis (mass-spectrometry, BioID, yeast two-hybrid), bioinformatics, genome editing (CRISPR-Cas9, Piggy-Bac transposase), dissection and manipulation of mouse embryos, molecular biological methods for gene cloning and analysis of gene expression (including real-time PCR and in situ hybridization), histology, immunofluorescence, cell culture, generation of mini-gut organoids, transfection, organoids, cell and embryo electroporation.

Eligibility:

Honours entry: GPA on track for Hons I / IIA classification             
PhD entry: Hons I classification, lab-based research experience is preferable.

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Keywords

mouse, Genetics, molecular biology, Development, regenerative medicine, Cancer, Endocrinology, Embryos, RNA, Stem cells, Organoids, CRISPR, gut

Opportunity ID

The opportunity ID for this research opportunity is: 2098

Other opportunities with Dr Nicolas Fossat

Other opportunities with Professor Patrick Tam