3D stem cell organoid models to investigate the phenotypic alterations induced by autism risk genes during early brain development

Research Opportunity
PhD students
Department / Centre
Paediatrics
Location
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
A/Prof Silvia Velasco silvia.velasco@mcri.edu.au

Summary Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by cognitive, motor, and sensory deficits. Despite hundreds of genes have been associated with risk for ASD, the phenotypic alterations in the developing human brain induced by ASD-risk gene mutation are not fully understood. Furthermore, mutant phenotypes in disease-associated genes vary across individuals. The recent emergence of stem-cell-derived 3D brain organoids represents a major advance in modelling the cellular complexity of the developing human brain and offers unprecedented opportunities to investigate neurodevelopmental abnormalities associated with mutation in ASD-risk genes. The histone methyltransferase KMT5B has emerged repeatedly as top hit in studies of ASD genetic risk, and is associated with severe neurodevelopmental abnormalities, including macrocephaly, in patients. However, the biological function of KMT5B during human brain development is largely unknown.

Project Details

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by cognitive, motor, and sensory deficits. Despite hundreds of genes have been associated with risk for ASD, the phenotypic alterations in the developing human brain induced by ASD-risk gene mutation are not fully understood. Furthermore, mutant phenotypes in disease-associated genes vary across individuals. The recent emergence of stem-cell-derived 3D brain organoids represents a major advance in modelling the cellular complexity of the developing human brain and offers unprecedented opportunities to investigate neurodevelopmental abnormalities associated with mutation in ASD-risk genes. The histone methyltransferase KMT5Bs emerged repeatedly as top hit in studies of ASD genetic risk, and is associated with severe neurodevelopmental abnormalities, including macrocephaly, in patients. However, the biological function of KMT5B during human brain development is largely unknown.

In this project, we propose to leverage a 3D model of the developing cerebral cortex (cortical organoids), that we recently established, to identify ASD-specific developmental abnormalities associated with haploinsufficiency in KMT5B gene. By taking advantage of innovative single-cell-omics technologies, we aim to unbiasedly discover the transcriptional, morphological, and electrophysiological changes induced by KMT5B loss of function during early cortical development, and identify the molecular mechanisms involved. This work, through the identification of the specific cell types affected, molecular processes involved, and functional features compromised, will yield novel insights into the role of KMT5B in the pathogenesis of ASD and will provide an experimental paradigm for investigating the contribution of additional genes to neurodevelopmental disorders. The acquired knowledge will provide a readout to develop a robust model system for the screening of candidate compounds and find new action strategies for ASD and neurodevelopmental disorders.

The prospective candidate will get the opportunity to learn a variety of laboratory techniques, including stem cell culturing, differentiation into 3D brain organoids, immunohistochemistry, microscopy, real time PCR, western blotting, in addition to a range of single-cell genomic technologies.



Faculty Research Themes

School Research Themes

Child Health in Medicine



Research Opportunities

PhD students
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department / Centre

Paediatrics

Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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