Journal
ANNALS OF NEUROLOGY
Volume 60, Issue 1, Pages 137-144Publisher
WILEY-LISS
DOI: 10.1002/ana.20843
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Funding
- NIMH NIH HHS [1K08MH/NS63886-01, K08 MH063886] Funding Source: Medline
- NINDS NIH HHS [R01 NS047191, 1P01NS40043, 2R37 NS35129] Funding Source: Medline
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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.
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