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Published on: August 23, 2016
Impaired proliferation and migration in human Miller-Dieker neural precursors
Volney L Sheen1, Russell J Ferland, Megan Harney
1Department of Neurology, Division of Neurogenetics and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. vsheen@bidmc.harvard.edu
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.
Insights
Miller-Dieker syndrome (MDS) involves a smooth brain (lissencephaly) due to chromosome 17p13.3 deletions. Human neural precursors from MDS tissue revealed impaired neuronal migration, reduced proliferation, and increased cell death, suggesting proliferation defects contribute to lissencephaly.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Miller-Dieker syndrome (MDS) is a human developmental brain disorder characterized by lissencephaly (smooth brain).
- It is caused by heterozygous deletions on chromosome 17p13.3, encompassing the lissencephaly 1 (LIS1) gene.
- Existing mouse models have limitations for studying human lissencephaly due to natural mouse lissencephaly.
Purpose of the Study:
- To establish human neural precursor cell lines from postmortem Miller-Dieker syndrome (MDS) tissue.
- To characterize the cellular pathologies contributing to the human lissencephalic phenotype in MDS.
Main Methods:
- Human neural precursors were isolated from postmortem frontal cortex tissue of an MDS fetus and an age-matched control.
- In vitro assays assessed proliferation and cell death rates.
- In vivo transplantation examined precursor cell migration.
Main Results:
- MDS precursors exhibited LIS1 gene haploinsufficiency and reduced LIS1 protein levels.
- These precursors could differentiate into neurons and glia.
- MDS precursors showed impaired neuronal migration, decreased proliferation, and increased cell death.
Conclusions:
- Disruptions in cell proliferation may play a significant role in lissencephaly development, beyond previously emphasized migration defects.
- These findings highlight the importance of studying human cell models for understanding human neurodevelopmental disorders.
