, 2004, Kim et al., 2006 and Soderling et al., 2007), loss of FMRP ( Comery et al., 1997, Cruz-Martín et al., 2010, Galvez and Greenough, 2005 and Irwin et al., 2002), overexpression of ARC ( Peebles et al., 2010), or Rac1 blockade during early development ( Tashiro and Yuste, 2004). All these phenotypes overlap, without being identical, indicating that CYFIP1 is at the hub of more than one spine-controlling pathway. Spine dysmorphogenesis is a common feature of several neuropsychiatric disorders (Penzes et al., 2011). Of note, FMRP- and CYFIP1-linked disorders are characterized by spine dysmorphogenesis selleck chemical that we show here is caused by an imbalance of protein synthesis
and actin remodeling. CYFIP1 is implicated in ID ( Cooper et al., 2011, Napoli et al., 2008, Nowicki et al., 2007 and Schenck et al., 2003), ASD ( Cooper et al., 2011, Doornbos et al., 2009, Murthy et al., 2007, Nishimura et al., 2007, Sahoo et al., 2006, van der Zwaag et al., 2010 and von der Lippe et al., 2010), and SCZ ( Tam et al., 2010 and Zhao et al., 2012). Consistently with the idea that related human disorders might share genetic causes
because they are due to perturbations of highly interconnected cellular networks ( Vidal et al., 2011), we find that the CYFIP1 interactome is enriched in genes implicated in ID, ASD, SCZ, ADHD, MDD, and AD. Importantly, the two key CYFIP1 interactors examined here, NCKAP1 and eIF4E, have been shown to be genetically associated with ASD ( Iossifov et al., 2012 and Neves-Pereira et al., 2009). Our findings suggest that mutations in the CYFIP1 network
might explain part of the autistic features Protein Tyrosine Kinase inhibitor observed in FXS patients ( Farzin et al., 2006), which can also suffer from psychosis ( Reiss et al., 1986). Mutations in the genes of the CYFIP1 interactome might perturb the homeostasis of the interaction networks, regulating translation versus cytoskeleton remodeling, thereby triggering a spectrum of pathological processes at synapses that can lead to a broad range of clinical manifestations, such as intellectual disabilities, autism, and schizophrenia. Animal care was conducted according to the Belgian law of August 14th, 1986, concerning the protection and well-being very of animals, and the following Koninklijk Besluit (K.B.) of November 14th, 1993 and K.B of September 13th, 2004, as well as to the European Community Council Directive 86/609, Oja L 358, 1, December 12, 1987, and international guidelines (European Community Council Directive 86/609, Oja L 358, 1, December 12, 1987; National Institutes of Health Guide for the Care and Use of Laboratory Animals, US National Research Council, 1996). One-month-old C57BL/6J Fmr1 KO and WT control littermates were used for the EM-IHC control. WT mice used in this study were 3- to 4-week-old males C57BL/6J. Two-month-old Cyfip1+/− 129/Sv C57BL/6J and WT control littermates were used for diolistic staining on brain slices.