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Chromosomal aneuploidy in the developing mammalian cortex


Although aneuploidy, variations in chromosome number from haploid genome multiples, is a feature of several nervous system diseases, aneuploid cells have been found in the non-diseased developing and adult brain. This genetic mosaicism may contribute to the phenotypic and functional diversity in the central nervous system. This dissertation aims to characterize aneuploidy in embryonic cortical neural progenitor cells (NPCs) over a time frame that coincides with neurogenesis, and to identify functional consequences of this phenomenon. As neurogenesis proceeds, neurons are produced from two genetically distinct progenitor populations. In the studies described in Chapter 2, we tested the hypothesis that these molecular differences will be reflected in changes in the rate of aneuploidy in the developing cortex. Metaphase spread analysis and fluorescence in situ hybridization determined that aneuploid NPCs were present throughout neurogenesis, with peak levels found in dividing cells during the middle stage of neurogenesis. Our results revealed that lagging chromosomes, a mitotic defect that leads to aneuploidy, are evident in various stages of embryonic cortical development. The finding that aneuploidy increases during stages of cortical development when the most functionally and phenotypically varied cortical projection neurons are produced suggests that there is positive selection for cells with favorable aberrant karyotypes as a means of generating a great amount of diversity in a limited time. Loss of heterozygosity (LOH) represents inactivation of a wild-type allele that renders the cell homozygous or hemizygous for a deleterious allele. Given that hyperploidy is the most common form of aneuploidy observed in NPCs, it is likely that LOH via chromosome loss may lead to changes in the developing brain. The analyses outlined in Chapter 3 determined whether mosaic aneuploidy, through LOH, influences leukemia inhibitory factor receptor (LIFR)-mediated astrocyte differentiation of NPCs. Using flow cytometry, we have shown that loss of chromosome 15, on which the LIFR allele resides, reduced the ability of cortical NPCs to generate astrocytes in response to ciliary neurotrophic factor (CNTF). In summary, this work demonstrates that aneuploidy is a normal feature of NPCs across cortical neurogenesis, and one potential outcome of this variation is a change in the balance of neural and glial cell fates

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