Role of Slit and Robo in the development of midline glia and corpus callosum

Divya Unni (2010). Role of Slit and Robo in the development of midline glia and corpus callosum PhD Thesis, Queensland Brain Institute, The University of Queensland.

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Author Divya Unni
Thesis Title Role of Slit and Robo in the development of midline glia and corpus callosum
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2010-09
Thesis type PhD Thesis
Supervisor Linda Richards
Total pages 144
Total colour pages 12
Total black and white pages 132
Subjects 06 Biological Sciences
Abstract/Summary Slits, a family of secreted proteins, are crucial for axon guidance during the development of the central nervous system. In rats, Slit1, Slit2 and Slit3 mRNA are expressed in midline glial populations surrounding the developing corpus callosum (Marillat et al., 2002). A previous study has shown that mice lacking the Slit2 gene have an acallosal phenotype (Bagri et al., 2002). However, the role of Slit1 and Slit3 in the development of the corpus callosum is unknown. In the present study expression analysis of Slit1, Slit2 and Slit3 mRNA performed on mice, showed that these molecules were expressed around the developing corpus callosum. To understand the role each Slit might play in the development of the corpus callosum, 4 Slit mutant mouse strains, Slit1-/-, Slit2-/-, Slit1-/-;Slit2-/- and Slit3-/- mice were analysed. This study confirmed that Slit2-/- mice displayed dysgenesis of the corpus callosum across its rostro-caudal extent. Mice lacking the Slit1 gene did not exhibit an acallosal phenotype, however, Slit1-/-;Slit2-/- mice displayed a more severe phenotype compared to mice deficient in Slit2 alone, indicating a role for Slit1 in corpus callosum development. A subset of the Slit3-/- mice displayed an axon guidance defect in the corpus callosum, where the callosal axons in the dorsal region of the tract failed to cross the midline. This defect was observed in embryonic as well as postnatal ages. The callosal axon guidance defects in Slit2-/- and Slit1-/-;Slit2-/- mice were also observed at earlier stages during the development of the cingulate pioneering axons of the corpus callosum. Apart from axon guidance Slit1, Slit2 and Slit3 were involved in the development of the glial populations at the midline of the cerebral cortex. Slit2-/- and Slit1-/-;Slit2-/- mice exhibited a positional defect where the indusium griseum glia was ventrally displaced. The glial-positioning defect in Slit1-/-;Slit2-/- mice was more severe compared to Slit2-/- mice. No positional defect was observed in Slit3-/- mice, however the development of the indusium griseum glia was affected. To compare the axon guidance phenotype of the Slit2-/- mice, and the knockout of its known receptor Robo1-/- mice, diffusion tensor magnetic resonance imaging and tractography was performed on Slit2-/-, and Robo1-/- mice. These experiments showed that the axon guidance defect in Slit2-/- mice is similar, but more severe compared to Robo1-/- mice. The axons of the CC are displaced rostrocaudally in both Slit2-/- and Robo1-/- mice. In Robo1-/- mice only the pre-crossing axons are affected while in Slit2-/- mice both the pre-crossing as well as post-crossing axons are affected. These results suggest a possible role for Slit in the development of the telencephalic midline, where it is first involved in the proper positioning and development of the midline glial populations and then acts as an axon guidance molecule for the crossing of callosal axons to their homotypic targets in the contralateral hemisphere.
Keyword Slit, Robo, Glia, Corpus callosum
Additional Notes 23, 43, 58, 69, 85, 100, 102, 105, 114, 119, 121, 131

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Created: Wed, 29 Sep 2010, 10:51:17 EST by Ms Divya Unni on behalf of Library - Information Access Service