Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development

Abstract

Fragile X syndrome is caused by the lack of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA transport and translation. FMRP is a component of mRNA ribonucleoprotein complexes and it can interact with a range of proteins either directly or indirectly, as demonstrated by two-hybrid selection and co-immunoprecipitation, respectively. Most of FMRP-interacting proteins are RNA-binding proteins such as FXR1P, FXR2P and 82-FIP. Interestingly, FMRP can also interact directly with the cytoplasmic proteins CYFIP1 and CYFIP2, which do not bind RNA and link FMRP to the RhoGTPase pathway. The interaction with these different proteins may modulate the functions of FMRP by influencing its affinity to RNA and by affecting the FMRP ability of cytoskeleton remodeling through Rho/Rac GTPases. To better define the relationship of FMRP with its interacting proteins during brain development, we have analyzed the expression pattern of FMRP and its interacting proteins in the cortex, striatum, hippocampus and cerebellum at different ages in wild type (WT) mice. FMRP and FXR2P were strongly expressed during the first week and gradually decreased thereafter, more rapidly in the cerebellum than in the cortex. FXR1P was also expressed early and showed a reduction at later stages of development with a similar developmental pattern in these two regions. CYFIP1 was expressed at all ages and peaked in the third post-natal week. In contrast, CYFIP2 and 82-FIP (only in forebrain regions) were moderately expressed at P3 and gradually increased after P7. In general, the expression pattern of each protein was similar in the regions examined, except for 82-FIP, which exhibited a strong expression at P3 and low levels at later developmental stages in the cerebellum. Our data indicate that FMRP and its interacting proteins have distinct developmental patterns of expression and suggest that FMRP may be preferentially associated to certain proteins in early and late developmental periods. In particular, the RNA-binding and cytoskeleton remodeling functions of FMRP may be differently modulated during development.

FMRP Mediates Chronic Ethanol‐Induced Changes in NMDA, Kv4.2, and KChIP3 Expression in the Hippocampus

“…Disruption of FMRP expression and function leads to dysregulation of activity-dependent local translation, and affects neuronal mechanisms of plasticity (Wang et al, 2014, Yun and Trommer, 2011). While the importance of FMRP during development has been well established, a potential role for FMRP in mediating alterations in translation in response to chronic ethanol exposure is not known (Saffary and Xie, 2011, Fernandez et al, 2013, Bonaccorso et al, 2015). The goal of the current study was to gain a better understand the role of FMRP in regulating ethanol-induced changes in protein expression at glutamatergic synapses.…”

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

“…Some findings from other laboratories are in line with our results. Indeed, (i) while both CYFIP1 and CYFIP2 interact with FMRP, only CYFIP2 interacts with FXR1P and FXR2P, the two paralogs and interactors of FMRP (Schenck et al, 2001); (ii) the expression of the two proteins appears differently modulated in different brain regions during post-natal brain development, while the three FXR proteins have the same expression pattern during development (Bonaccorso et al, 2015); (iii) depletion of CYFIP1 in epithelial cancer cells interferes with the morphology of the cells and induces invasion (Silva et al, 2009). This phenotype is also present when WAVE1 or NAP1 are knocked down.…”

“…CYFIP1 and CYFIP2 are members of a family of proteins interacting with the Fragile X mental retardation protein (FMRP, encoded by FMR1 ) in mammals, as well as in the fly (Abekhoukh and Bardoni, 2014; Schenck et al, 2001, 2003). They have different patterns of expression during brain development (Bonaccorso et al, 2015) and while CYFIP1 interacts only with FMRP, CYFIP2 is also a partner of the two other members of the Fragile X-related protein (FXR) family, namely FXR1P and FXR2P. 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).…”

“…While a few studies have linked the CYFIP family genes to carcinogenesis (Silva et al, 2009), a large number of studies focused on the role of these proteins both within neurons and during neuronal development (Abekhoukh and Bardoni, 2014; Bonaccorso et al, 2015) because of the functional links of these proteins to neurodevelopmental disorders such as ID, autism, schizophrenia or epilepsy (Schenck et al, 2001, 2003; Madrigal et al, 2012; Wang et al, 2015; Waltes et al, 2014; De Rubeis et al, 2013; Huang, 2016). CYFIP1 is localized in the BP1-BP2 region of human chromosome 15q11.2 (Abekhoukh and Bardoni, 2014) and deletion of this region (including the NIPA1 , NIPA2 , TUBGCP5 and WHAM genes) leads to the Burnside-Butler (BP1-BP2 microdeletion) syndrome, characterized by developmental and language delay, neurobehavioral disturbances and psychiatric problems, autism, seizures, schizophrenia and mild dysmorphic features (Cox and Butler, 2015).…”

Fragile X Mental Retardation Protein Requirements in Activity-Dependent Critical Period Neural Circuit Refinement

“…In addition to low IQ and learning disabilities, FXS patients exhibit hypersensitivity to multiple sensory modalities [1], and up to 20% comorbidity for childhood epilepsy [3]. Fragile X Mental Retardation Protein (FMRP) expression delineates early-use critical periods of neural circuit optimization in FXS disease models [4,5]. FMRP is proposed to function within the activity sensor mechanism, mediating activity-dependent synaptic remodeling based on early sensory experience [6,7].…”