Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity

Abstract

SUMMARY Defects in brain development are believed to contribute towards on-set of neuropsychiatric disorders but identifying specific underlying mechanisms has proven difficult. Here, we took a multi-faceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signalling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

Low-Density Neuronal Cultures from Human Induced Pluripotent Stem Cells

“…Altered differentiation patterns in neuronal and glial lineages of human iPSCs bearing the 15q11.2 (BP1-BP2) deletion have been reported by other groups [19]. This deletion is associated with several neuropsychiatric disorders, including autism, schizophrenia, and intellectual disability [20].…”

Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs)

“…Subject selection criteria vary in these studies, spanning from specific genetic abnormalities like CNVs such as 22q11.2 deletion [38–40], 15q11.2 deletion [41] or CNTNAP2 deletion [42] and mutations such as DISC1 mutation [43,44] to SCZ patients with no identified genetic risk factor drawn from clinical populations [45–48]. Childhood onset SCZ (COS) [49], has also been studied since COS exhibits more severe psychopathology as compared to adult onset SCZ and thus would likely have a more robust cellular phenotype.…”

“…In these studies, the neural populations generated, range from neural progenitor cells (NPC) [41–43,45,46,48,49,52] to mixed neural populations [38–40,47,53] and to more specific neural subtypes such as highly enriched glutamatergic neurons [44]. These iPSC-derived neural populations recapitulate the normal developmental time frame and more closely resemble fetal neural progenitors and neuronal populations, suitable for analysis of developmental abnormalities.…”

A dangerous method? The use of induced pluripotent stem cells as a model for schizophrenia

“…The use of iPSCs to model schizophrenia has so far generated as much controversy and internal disagreement as it has interest Wen et al, 2014;Paulsen et al, 2012;Robicsek et al, 2013;Yu et al, 2014;Hook et al, 2014;Hartley et al, 2015;Hashimoto-Torii et al, 2014;Paulsen et al, 2014;Topol et al, in press;Yoon et al, 2014) (Appendix 1). Before this field begins to really deliver on its promises, there are several theoretical and methodological questions that need answering.…”

“…4) The mitochondrial membrane potential has a lower magnitude in SCZ NPCs, GluNs, and DaNs compared to control equivalent neural cells 5) The distribution of mitochdonria inside neurons is more variable is SCZ NPCs, GluNs, and DaNs compared Frequency, but not amplitude, of spontaneous synaptic currents is decreased → presynaptic release defects 3) TALEN genome-editing shows that the DISC1 mutation is necessary and sufficient for these changes 4) Schizophrenia neurons show widespread transcriptional disturbancesYoon et al, 2014 …”