Brain Development Laboratory
Group Leader
Professor Seong-Seng Tan BDS (Malaya)
MDS (Adelaide)
D.Phil (Oxford)
FRACDS (Australia)
Contact Details
Email: | |
Phone: | +61 (0)3 8344 1958 |
web: |
Number of
Staff: 10
Students: 3
Research Interests
The Brain Development Laboratory is interested in
- understanding how brain cells are properly assembled during development. Specifically, we wish to enquire how individual neurons in the embryonic brain know where to go and what to become.
- Learning the identities of genes that drive neuronal migration and testing the functions of these genes in the intact brain. For instance, how do these genes alter the way cells are born, change shape, migrate and adopt different neuronal identities? These studies will provide new information on how genes have shaped brain evolution. Understanding the link between genetic mutations and aberrant neuronal behaviour can also explain the genetic causes of mental illness such as autism, schizophrenia and epilepsy.
- Discovering how to prolong the survival of neurons after injury and stress in situations following stroke or brain trauma. We have discovered a number of neuroprotective proteins and wish to uncover the mechanisms of their action, and devise methods of delivering them to stressed neurons.
Current Projects
How do interneurons find their destinations?
We are investigating how cortical interneurons are able to find their proper locations after long-range tangential migration from the subcortical ganglionic eminence. More specifically, Vicki Hammond and Frank Weissenborn have questioned whether or not the molecules of the Reelin-signalling pathway (RSP) play major roles in interneuron positioning. We have found that interneurons in different cortical layers have non-equivalent patterns of responsiveness to RSP – while early-born interneurons are not dependent on RSP, late-born interneurons require RSP for proper positioning. Further research is targeted at understanding how Reelin exerts its function in both interneurons and projection neurons. Fiona Christensen is involved in the geneneration of mouse chimaeras to address these questions.
What factors control the movement of cortical interneurons?
How interneurons migrate may hold the key to understanding certain brain disorders such as epilepsy and schizophrenia arise. Joanne Britto with Karen Tait have established a video-imaging technique that allows migrating interneurons to be captured live under confocal microscopy. Together with Leigh Johnston, this project has generated new information to suggest that interneurons employ various strategies to reach their target destination. Leigh Johnston has used this data to develop a biomechanical mathematical model that is formulated according to the principle of conservation of momentum in dynamic systems. This model, based on Newtonian laws of motion, provides a testable simulation of interneuron migration and is the first known mathematical depiction of interneuron migration.
The function of Sez-6 during neuronal branching
After migrating neurons have reached their layer destinations, it is important for them to commence the process of wiring to other neurons. Jenny Gunnersen, with Stephanie Fuller, has been studying this process with special interests in understanding how a neuron achieves the correct balance between extending too many or too few dendrites. The Sez-6 appears to be an important player in the elaboration of dendritic trees. To study this, we have deleted the Sez-6 gene in mice by gene-targeting in embryonic stem cells. These studies now firmly establish that Sez-6 is important for contraining excessive dendrite formation, and in the absence of Sez-6, neurons in the cortex display exuberant dendritic outgrowth.
Protein ubiquitination as a mechanism for improving neuronal survival in brain injury
Brain injury from trauma is a major health issue in Australia. Each year, about 3,000 patients are admitted to hospital with traumatic brain injury. About 10% of these have moderate to severe brain trauma leading to long-term physical, behavioural and cognitive deficits. We have been looking for mechanisms to limit neuronal cell death following injury by saving “what’s left behind”, providing the patient with a better foundation for recovery. This search has uncovered a novel protein, Ndfip1 that protects neurons from death. Qian Sang is generating a knock-out mouse to study the role of Ndfip1 in neuroprotection. To test whether or not Ndifp1 acts as a scavenger for damaged proteins, Jason Howitt and Katerina Viduka are studying mechanisms of Ndfip1 function using cultured cell lines. In order to deliver Ndfip1 to stressed neurons, Ulrich Putz is devising delivery systems based on lentiviral vectors. In addition, Jenny Lackovic has uncovered new evidence to suggest that Ndfip1 expression is also neuroprotective during stroke.
Laboratory Techniques
- Gene targeting and transgenic mice
- Lentiviral gene transfer
- Confocal video microscopy
- Molecular biology and biochemistry
- Brain tissue transplantation
Funding
- National Health & Medical Research Council (Australia)
- Program grant: S-S Tan (P. Bartlett, T. Kilpatrick, P. Sah).
Title of project: Regulation of neural cell production in the normal and diseased brain. - Project grant: J Gunnersen and V. Hammond
Title of project: Genetic cues responsible for interneuron migration and layering in the neocortex - Project grant: J Gunnersen, V. Hammond and J. Britto
Title of project: Sez-6 protein: signalling mechanisms and function in the developing neocortex - Project grant: J. Britto, V. Hammond and S-S Tan
Title of project: The role of Reelin-signalling on cortical neuron migration
- Program grant: S-S Tan (P. Bartlett, T. Kilpatrick, P. Sah).
- Victorian Neurotrauma Initiative
- Program Grant: S-S Tan (with D. Vaux, J. Silke, S. Kumar, C. Morganti-Kossmann, T. Kossman)
Title of project: Preventing neuronal cell death following brain Trauma
- Program Grant: S-S Tan (with D. Vaux, J. Silke, S. Kumar, C. Morganti-Kossmann, T. Kossman)
Additional Information
Seong-Seng Tan is on the Editorial Board of the following journals:
- Journal for Neuroscience (USA)
- Experimental Neurology (USA)
- Journal of Anatomy (GB)
Research
