New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes

Abstract

Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its Drosophila homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of CYFIP1 and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models – fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…A recent gene expression study shows JAKMIP1 modulates microtubule transport and GABA B R levels [32]. WAVE complex CYFIP1 links FMRP to actin regulation, and mechanistic target of rapamycin (mTor) signaling in both mice and Drosophila [45]. A FMRP/CYFIP1/Staufen complex recruited by TAR DNA binding protein 43kDa (TDP-43) represses the translation of Ras-related C3 botulinum toxin substrate 1 (Rac1), microtubule-associated protein 1B (MAP1B) and glutamate receptor 1 (GluR1) to limit spinogenesis in mice and human cell lines (Table 2) [34,40].…”

Persistent Cyfip1 expression is required to maintain the adult subventricular zone neurogenic niche

“…In this study, we demonstrate that Cyfip1 is important for the proper establishment and maintenance of the adult SVZ niche architecture and the regulation of type B1 cell proliferation and localization. While the importance of Cyfip1 in embryonic development as well as mature neuronal plasticity is beginning to be appreciated (Abekhoukh and Bardoni, 2014;Abekhoukh et al, 2017;Yoon et al, 2014;De Rubeis et al, 2013a), this study is the first to suggest that Cyfip1 is a critical component for establishing and maintaining the adult NSC niche and regulating NSC fate. Our study further suggests that type B1 adult NSCs maintain the capacity for symmetric self-renewal to amplify their pool in the adult brain.…”

“…Copy number variation in the 15q11.2 locus also results in changes in white matter microstructure (Silva, A. I. et al, 2019). The role of Cyfip1 as a member of the WAVE regulatory complex (WRC) in regulating actin nucleation makes it an ideal candidate to regulate synaptic plasticity as well as a regulator of early neural development (De Rubeis et al, 2013b;Abekhoukh et al, 2017;Yoon et al, 2014). Results presented here suggest that it continues to be important in postnatal NSC regulation with important downstream effects on postnatal neuron and oligodendrocyte genesis.…”

The Role of Protocadherin 19 (PCDH19) in Neurodevelopment and in the Pathophysiology of Early Infantile Epileptic Encephalopathy‐9 (EIEE9)

“…Neuronal migration and dendritic morphology are thus affected by PCDH19 loss of function; both events are fundamental for proper neuronal circuit formation and these observations confirm the relevance of PCDH19 during brain development. These data are paralleled by the observation that knockdown of Cyfip1 (one of the intracellular interactors of PCDH19, see above) in mouse cortical neurons similarly affects the complexity and the architecture of their dendritic arbors (Abekhoukh and Bardoni, ; Abekhoukh et al , ). Further, it has been shown a direct correlation between mRNA levels of Cyfip1 and those of WRC members and the importance, for WRC stability, of the correct stoichiometric relationship between its components: altered expression of one of WRC components impairs proper cell functions, like neuronal development and circuit formation (Abekhoukh et al , ).…”

“…These data are paralleled by the observation that knockdown of Cyfip1 (one of the intracellular interactors of PCDH19, see above) in mouse cortical neurons similarly affects the complexity and the architecture of their dendritic arbors (Abekhoukh and Bardoni, ; Abekhoukh et al , ). Further, it has been shown a direct correlation between mRNA levels of Cyfip1 and those of WRC members and the importance, for WRC stability, of the correct stoichiometric relationship between its components: altered expression of one of WRC components impairs proper cell functions, like neuronal development and circuit formation (Abekhoukh et al , ). Indeed, also the knockdown of WAVE‐1 causes a reduction of the extent of neurite outgrowth in mice hippocampal neurons and a reduction in spines density (Hazai et al , ; Soderling et al , ).…”