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OBJECTIVE: Miller-Dieker syndrome (MDS) is a malformation of cortical development that results in lissencephaly (meaning smooth brain). This disorder is caused by heterozygous deletions on chromosome 17p13.3, including the lissencephaly 1 (LIS1) gene. Various mouse models have been used as an experimental paradigm in understanding human lissencephaly, but clear limitations exist in these studies, particularly because mice are naturally lissencephalic. Thus, the objective of this article was to establish human neural precursor cell lines from postmortem MDS tissue and to characterize the pathological cellular processes that contribute to the human lissencephalic phenotype. METHODS: Human neural precursors were isolated and expanded from the frontal cortices of a 33-week postmortem fetus with MDS and an age-matched control subject. Relative rates of proliferation and cell death were assessed in vitro, whereas the migration of precursors was examined after transplantation in vivo. RESULTS: Precursors showed haploinsufficiency of the LIS1 gene and a reduction in LIS1 protein. Precursors could also differentiate into both neurons and glia. MDS precursors demonstrated impairments in neuronal migration, diminished rates of cell proliferation, and increased cell death. INTERPRETATION: These results suggest that, in addition to migration, disruption in cell proliferation could play a more important role in the development of lissencephaly than previously suspected.

Original publication

DOI

10.1002/ana.20843

Type

Journal article

Journal

Ann Neurol

Publication Date

07/2006

Volume

60

Pages

137 - 144

Keywords

1-Alkyl-2-acetylglycerophosphocholine Esterase, Cell Death, Cell Differentiation, Cell Division, Cell Line, Cell Movement, Cerebral Cortex, Chromosomes, Human, Pair 17, Fetus, Gene Deletion, Humans, Microtubule-Associated Proteins, Neuroglia, Neurons, Phenotype, Stem Cells