Project III: Study of human structural brain defects in zebrafish models
Vertebrate organogenesis is a complex process that is mediated by a coordinated set of cellular and molecular events. Analyzing these dynamic processes can be particularly difficult in mammalian animal models due to the development of mammalian embryos in utero. However, because of the optical clarity and external fertilization of zebrafish embryos/larvae, this vertebrate animal model system can be used to image in vivo the dynamic cellular processes of how specialized cells organize to become vertebrate organs. Exploiting these particularly useful imaging properties, the zebrafish community including our own lab has developed neural specific transgenic tools to further illuminate the dynamic cellular mechanisms that transform the neuroepithelium/neural tube into mature brain structures.
Utilizing these tools, we have initiated a forward genetic screen with the Gleeson Lab to identify novel SBD mutants which may provide further insight into the conserved mechanisms during brain morphogenesis. As a result, we have recovered SBD mutants with early brain defects that harbor mutations in genes that are in the cell polarity pathway further supporting the significance of cell polarization during brain morphogenesis. Because of the importance of polarity genes in establishing the cellular organization required for cell shape and movement, we hypothesize that cell polarity regulates the cell morphology and migration of neural cell lineages during CNS/brain development in order to direct overall brain morphogenesis and function.
The specific aims of Project III are:
- To uncover novel cell polarity pathways that may modulate CNS/brain morphogenesis and function
- To investigate SBD mutations discovered from human genetic studies and mouse forward genetic screens as described in Project I and II, respectively
- To investigate how cell polarity genes direct neural cell lineage morphology and migration
Overall, our interdisciplinary approach including use of a genetically tractable yet optically transparent animal system, innovative live imaging tools and techniques, and synergies with human and mouse genetic studies will provide in vivo mechanistic insight into how cell polarity may directly guide neurodevelopment.