Molecular Mechanisms Regulating the Development of the Corpus Callosum

Amber-lee Donahoo (2011). Molecular Mechanisms Regulating the Development of the Corpus Callosum PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Amber-lee Donahoo
Thesis Title Molecular Mechanisms Regulating the Development of the Corpus Callosum
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2011-07
Thesis type PhD Thesis
Supervisor Professor Linda Jane Richards
Dr Zlatko Pujic
Total pages 169
Total colour pages 37
Total black and white pages 132
Subjects 11 Medical and Health Sciences
Abstract/Summary The cerebral cortex is the area of the brain where higher-order cognitive processing occurs. In order to understand how the brain functions, it is imperative that we understand how the areas of the brain are connected and communicate with each other. The two hemispheres of the cerebral cortex are connected via one of the largest fibre tracts in the brain, the corpus callosum, which facilitates information transfer and processing. Due to its large size and dorsal position, the corpus callosum is also an excellent model for investigating how the brain wires up during development. In humans, malformation of the corpus callosum occurs in 1 in 4000 live-births and those afflicted experience an extensive range of neurological disorders, involving relatively mild to severe cognitive deficits. Understanding the molecular and cellular processes involved in these disorders would therefore assist in the development of prognostic tools and therapies for human acallosal syndromes. The axons of the corpus callosum connect the left and right cerebral hemispheres, but in order to do that, they must traverse the telencephalic midline, an environment enriched with molecular cues that direct the pathfinding of these axons. In the mouse, two populations of axons have been identified as comprising the corpus callosum, 1) the earliest projecting axons (termed the ‘pioneering axons of the corpus callosum’) that rise from the cingulate cortex, and 2) later projecting axons from the neocortex that constitute the bulk of this fibre tract. It is assumed that because these axons project within the same pathway and because the molecular composition of this midline region is relatively uniform during development that the molecular mechanisms used by the two populations are similar. However, the data discussed here suggest that this is incorrect, and that in fact the cingulate pioneering axons of the corpus callosum are regulated by separate mechanisms to those employed by the neocortical axons. To specifically identify the different molecular mechanisms active during the formation of the corpus callosum a number of candidate molecules were studied. Chapter 3 explores the cell-autonomous regulation of the corpus callosum by investigating the transcription factor, Emx1. This was achieved by in vivo phenotypic analyses of Emx1 transgenic mice and also by testing the response of callosal axons (from these mice) to guidance factors in an in vitro co-culture assay. Chapters 4 and 5 investigate the role of the secreted guidance molecule, Netrin1 (and its receptor, deleted in colorectal cancer, DCC) in the development of the corpus callosum using both in vivo phenotypic analysis of the Netrin1 and DCC mutant mice and in vitro co-culture assays designed to identify whether Netrin1 (classically known as an attractive guidance cue) specifically regulates the guidance of callosal axons. Chapter 6 investigates the guidance of neocortical callosal axons when in the presence of multiple guidance cues, specifically in the presence of Netrin1 and Slit2 (a repulsive guidance cue). In the spinal cord, the receptors for these ligands (DCC and Robo1 respectively) have been shown to interact in order to modify the response elicited by projecting axons, whether this effect is also observed in the neocortical axons of the corpus callosum was investigated. The results from this research highlight the complexity of the formation of connections between brain areas during development. In particular, they provide new insight into the molecular mechanisms that regulate the guidance of callosal axons through the intermediate target, the telecephalic midline. Novel evidence that the pioneering axons of a commissural system can be regulated by different mechanisms to those used by the later projecting axons was demonstrated. In particular, Emx1 and Netrin1 play a specific role in the guidance of the pioneering axons of the corpus callosum, whereas multiple cues (Netrin1, Slit2, DCC and Robo1) orchestrate the navigation of the later projecting neocortical axons of the corpus callosum through the telencephalic midline.
Keyword Axon Guidance
Forebrain Development
Corpus Callosum
Cingulate Cortex
Neocortex
Pioneering Axons
Netrin1
DCC
Slit2
Robo1
Emx1
Neuropilin1
Semaphorin3C
Additional Notes The pages that should be printed in colour include: 1, 21, 26, 27, 34, 60, 65, 67, 69, 71, 73, 75, 84, 86, 88, 90, 91, 94, 104, 106, 108, 111, 113, 123, 125, 127, 129, 132, 141, 147-154.

 
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Created: Wed, 14 Sep 2011, 13:20:01 EST by Mrs Amber-lee Donahoo on behalf of Library - Information Access Service