Protocadherin Mutations in Neurodevelopmental Disorders

Pham, Duyen; Tan, Chuan; Homan, Claire C.; Jolly, Lachlan A.; Gécz, Jozef

doi:10.1016/b978-0-12-800109-7.00014-5

Cited by 1 publication

(1 citation statement)

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“…CYFIP1 is involved in translational regulation by interacting not only with FMRP ( Schenck et al, 2001 ), but also with the translation initiation factor 4E ( Napoli et al, 2008 ; Beggs et al, 2015 ). More recently, the subcomplex including dCYFIP (the Drosophila ortholog of CYFIP1/2, also known as Sra-1 ) and Kette (ortholog of NAP1) has been reported to interact with a plethora of membrane proteins, including protocadherins, Roundabout (Robo) single-pass transmembrane receptors, protocadherins, netrin receptors, neuroligins, G-protein-coupled receptors and ion channels in the fly ( Chen et al, 2014 ; Pham et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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

Abekhoukh

Sahin

Grossi

et al. 2017

Disease Models &Amp; Mechanisms

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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.

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