Growing evidence suggests that Cytoplasmic FMR1 interacting protein 1 (CYFIP1), a little-studied molecule that maps to 15q11, may play an important role in autism spectrum disorders (ASDs). Change in dosage of CYFIP1 also appears to increase risk for schizophrenia, and is observed in one of the major gene causes of autism, (dup)15q11-13 syndrome. We have used microarrays to identify genes in monogenic forms of autism, contrasting genome-wide transcript levels from 15q, Fragile X, and typically developing individuals. These analyses indicated that CYFIP1 is up-regulated in both patient groups. Furthermore, small copy number variants (CNVs) encompassing CYFIP1 are present in ASD cases, but their pathogenicity remains unclear.
To ascertain how increased dosage at CYFIP may modulate brain development, we have generated models of Cyfip1 over-expression in vivo and in vitro. The approach permits empirical evaluation of how variation at CYFIP1 in particular may act to modulate risk and presentation in patients with duplications at 15q11.2 who have classic autism. We have begun to perform a morphological characterization of neurons models, dendritic arborization and morphology, and identify pathways that are altered by Cyfip1 expression changes.
We generated a panel of BAC transgenic mice in which copy number at CYFIP1 is elevated similar to patients (CYFIPbac). We established Cyfip1 over-expression and knockdown in mouse neural progenitor cells. We also performed Golgi staining of cortical neurons in adult mice for morphological analysis and reconstructed dendritic arbors by manual tracing (NeuroMath software).
The majority of pyramidal neurons in Layer V of CYFIP1bac mice showed shorter neurite length and larger cell soma, in addition to severe abnormalities of their dendritic spines. These results confirmed our original in vitro data that identified stunted dendritic arborizations.
The severity of the dendritic abnormalities suggests that they may be primary and cell automonous through the translational cascade, but further investigation is necessary. Eventually, we combined these pathological analyses with functional characterization. The key role of CYFIP1 in directly modulating activity dependent protein translation, which has also been suggested as an important convergent pathway in ASD, further emphasizes its potential central role in mediating at least some forms of ASD.
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