| Summary: | 碩士 === 國立陽明大學 === 生命科學系暨基因體科學研究所 === 103 === Abstract
Rab18 is a Ras-related small GTPase and has ubiquitous expression level predominantly in brain. Rab18 has been known to participate in lipid metabolism, Golgi-ER trafficking, and vesicle secretion. Loss-of-function mutation of rab18 causes Warburg micro syndrome, a developmental disorder accompanied by brain and eye deficits such as microphthalmia, microcephaly and cerebellar hypoplasia. In our study, significant cerebellar weight loss was found in Rab18 mutant (Rab18-/-) mice since born. Recent study of schizophrenia shows the association between cerebellar volume and Rab18 functions. We investigated the role of Rab18 in the development of cerebellum and found that the fissure between cerebellar lobule VI and lobule VII near vermis was less obvious in Rab18-/- mice. Given that Purkinje cells (PCs) and granule cells (GCs) play important roles in cerebellar foliation, we examined the differences of these neurons in Rab18-/- cerebella and discovered that PC number, but not density, and granular cell layer (GCL) thickness were reduced at P28. At P7, the expression level of sonic hedgehog protein (Shh), the proliferation signal for granule cell precursors secreted by PCs, was reduced in Rab18-/- cerebella. However, both number of BrdU-positive and PH3-positive granule cell precursors located in external granule cell layer (EGL) were increased in Rab18-/- cerebella. Aberrant migration and impaired ability to change cell shape of developing GCs was found as well. The processes of Bergmann glia, the crucial glia cells associated with migration of granule cells, were thickened in Rab18-/- mice. No significant differences of the thickness of molecular layer as well as the density of interneurons in molecular layer were found in Rab18-/- mice. Furthermore, the expression level of myelin basic protein (MBP), a myelination marker, and its distribution was less complex but more condensed in Rab18-/- cerebella than in wild-type. In older Rab18-/- mice, the phenotypes of PC degeneration were detected, including decreased PCs density and climbing fiber projection, less organized dendritic arborization, ER dilation and degenerating axonal terminal in deep cerebellar nuclei. In addition, the intensity of GFAP in the fibers of Bergmann glia was significantly augmented in the random molecular layer (ML) area Rab18-/- mice. Taken together, Rab18 is likely involved in the degeneration of Purkinje cells and proliferation, migration and cell shape change of granule cells during cerebellar development.
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