Impaired proliferation and migration in human Miller-Dieker neural precursors.
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.


CONCLUSIONS
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.
Sheen
Volney L
VL
Department 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
Ferland
Russell J
RJ
Harney
Megan
M
Hill
R Sean
RS
Neal
Jason
J
Banham
Alison H
AH
Brown
Philip
P
Chenn
Anjen
A
Corbo
Joseph
J
Hecht
Jonathan
J
Folkerth
Rebecca
R
Walsh
Christopher A
CA
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology*; D002886:Chromosomes, Human, Pair 17; D005333:Fetus / Q000166:cytology; D017353:Gene Deletion; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology; D010641:Phenotype; D013234:Stem Cells / Q000473:pathology*
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse