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Schizophrenia: Risky neurodevelopment

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The 15q11.2 microdeletion is among the most frequent copy number variations associated with increased risk for schizophrenia. A recent study using human induced pluripotent stem cells (iPSCs) has identified CYFIP1, one of four genes in this locus, to be a modulator of cell polarity and a regulator of maintenance of adherens junctions (Cell Stem Cell 15, 79–91, 2014).

Yoon et al. established iPSC lines from three individuals with the 15q11.2 microdeletion and subsequently derived neurons from the iPSCs. The neurons displayed abnormal apical polarity and adherens junctions due to the haploinsufficiency of the CYFIP1 gene. CYFIP1 forms a part of the actin-modulating WAVE complex, which the authors found is destabilized in the mutant cells.

Knockdown of Cyfip1 in the neocortex of mice at embryonic day 13.5 indicated that CYFIP1 regulates apical polarity and adherens junction in radial glial stem cells. Biochemical and immunohistochemistry studies indicated that CYFIP1 is involved in cortical development through WAVE signaling.

A human genetic association study including four single nucleotide polymorphisms (SNPs) that altered expression of WAVE pathway–related genes indicated that these SNPs are not themselves risk factors. However, there is increased risk for schizophrenia depending on the genotypes at two of the SNPs, indicating an epistatic interaction.

This study suggests a biological mechanism for a common schizophrenia risk factor. However, it remains to be seen whether WAVE signaling directly regulates cortical development in humans.

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Carr, F. Schizophrenia: Risky neurodevelopment. Nat Med 20, 813 (2014). https://doi.org/10.1038/nm.3661

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