Mol Psychiatry. 2017 Sep 19. doi: 10.1038/mp.2017.175. [Epub ahead of print]

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

Shahsavani M¹, Pronk RJ¹, Falk R¹, Lam M¹, Moslem M¹, Linker SB², Salma J¹, Day K¹, Schuster J³, Anderlid BM⁴, Dahl N³, Gage FH², Falk A¹.

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.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.175.