Abstract
The cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) gene is associated with epilepsy, intellectual disability (ID), and developmental delay, suggesting its critical role in proper neuronal development and function. CYFIP2 is involved in regulating cellular actin dynamics and also interacts with RNA-binding proteins. However, the adult brain function of CYFIP2 remains unclear because investigations thus far are limited to Cyfip2 heterozygous (Cyfip2+/−) mice owing to the perinatal lethality of Cyfip2-null mice. Therefore, we generated Cyfip2 conditional knock-out (cKO) mice with reduced CYFIP2 expression in postnatal forebrain excitatory neurons (CaMKIIα-Cre). We found that in the medial prefrontal cortex (mPFC) of adult Cyfip2 cKO mice, CYFIP2 expression was decreased in both layer 2/3 (L2/3) and layer 5 (L5) neurons, unlike the L5-specific CYFIP2 reduction observed in adult Cyfip2+/− mice. Nevertheless, filamentous actin (F-actin) levels were increased only in L5 of Cyfip2 cKO mPFC possibly because of a compensatory increase in CYFIP1, the other member of CYFIP family, in L2/3 neurons. Abnormal dendritic spines on basal, but not on apical, dendrites were consistently observed in L5 neurons of Cyfip2 cKO mPFC. Meanwhile, neuronal excitability and activity were enhanced in both L2/3 and L5 neurons of Cyfip2 cKO mPFC, suggesting that CYFIP2 functions of regulating F-actin and excitability/activity may be mediated through independent mechanisms. Unexpectedly, adult Cyfip2 cKO mice did not display locomotor hyperactivity or reduced anxiety observed in Cyfip2+/− mice. Instead, both exhibited enhanced social dominance accessed by the tube test. Together, these results provide additional insights into the functions of CYFIP2 in the adult brain.
Highlights
Two members of the cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein family, CYFIP1 and CYFIP2, are evolutionarily highly conserved proteins which were originally identified as direct binding partners of FMR Protein (Schenck et al, 2001), an RNA-binding protein whose loss causes fragile X syndrome (Bagni and Zukin, 2019)
At the protein level, reduced expression of CYFIP2 and WAVE1 was observed in whole lysates of the cortex, striatum, and hippocampus but not the cerebellum of adult Cyfip2 conditional knock-out (cKO) mice (Figures 1C–F), which is consistent with previous studies showing that Wiskott–Aldrich syndrome protein family verprolin-homologous protein (WAVE) protein in the WRC becomes less stable and is degraded by the proteasome without CYFIP (Kunda et al, 2003; Zhao et al, 2013; Han et al, 2015)
CYFIP1 protein expression was increased in the cortex, but not in other brain regions, of Cyfip2 cKO mice (Figure 1C), suggesting a potential compensatory response of CYFIP1 in the cortex owing to a reduction in CYFIP2
Summary
Two members of the cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein family, CYFIP1 and CYFIP2 ( referred to as SRA1 and PIR121, respectively), are evolutionarily highly conserved proteins which were originally identified as direct binding partners of FMR Protein (Schenck et al, 2001), an RNA-binding protein whose loss causes fragile X syndrome (Bagni and Zukin, 2019). At least for survival, CYFIP1 and CYFIP2 cannot compensate for each other considering Cyfip1null mice (Chung et al, 2015) and Cyfip2-null mice (Kumar et al, 2013; Han et al, 2015; Zhang et al, 2018) are nonviable owing to lethality at different developmental time points (early embryonic and perinatal lethality, respectively). Both CYFIP1 and CYFIP2 genes are associated with various brain disorders (Abekhoukh and Bardoni, 2014; Zhang et al, 2019b). Cyfip cKO mice displayed many of the common phenotypes that are observed in Cyfip2+/− mice, but with some distinct molecular, cellular, and behavioral abnormalities, providing additional insights into understanding the in vivo brain functions of CYFIP2
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