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Mol Psychiatry. 2018 Jul;23(7):1674-1684. doi: 10.1038/mp.2017.175. Epub 2017 Sep 19.

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis.

Author information

1
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
2
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA.
3
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
4
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
5
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Anna.falk@ki.se.

Abstract

Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.

PMID:
28924182
DOI:
10.1038/mp.2017.175
[Indexed for MEDLINE]

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