Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by the lack 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 [1], including other RNA-binding proteins, such as the Fragile X related (FXR) proteins FXR1P and FXR2P. These two proteins are very similar to FMRP in their overall structure, being characterized by the presence of two KH, one RGG box RNA binding domain and nuclear localization and export signals (NLS and NES); however, their functions in the brain is much less characterized than FMRP. It has been proposed that the interaction between FXR1P and FMRP may change the affinity of FMRP for its target mRNAs with possible functional consequences for FMRP-mediated regulation of transport and translation [2]. Activation of group-I metabotropic glutamate (mGlu) receptors triggers the rapid translation of mRNAs, a mechanism implicated in synaptic plasticity and dysregulated in FXS [3]. To better understand the function of FXR1P and FXR2P in the brain and the link between mGlu5 receptor activation and FMRP function in the context of the multimolecular complex containing FXR proteins, we studied: i) the expression of FMRP, FXR1P and FXR2P in different brain areas during development in WT and Fmr1 KO mice; ii) the interaction between FMRP and FXR1P and FXR2P, and the possible modulation of these interactions by activation of mGlu5 receptors. FMRP, FXR1P and FXR2P exhibited a similar decrement of expression during development in different brain areas of WT and KO mice. The exposure of cortical slices (P14) to the group-I mGlu receptors agonist DHPG (100 mM) for 5 minutes reduced the reciprocal interaction of FRAX related proteins in both WT and KO mice, an effect antagonized by the mGlu5 receptor antagonist MPEP (3 mM). We are currently investigating different signal transduction pathways responsible for this mGlu5-mediated modulation of FMRP/ FXR1P/FXR2P interaction. Our data suggest that FMRP/FXR1P/FXR2P interaction plays a role during development and that the activation of mGlu5 receptors might influence the functions of FMRP and its related proteins by modulating their reciprocal interaction.
Metabotropic Glutamate Subtype 5 (mGlu5) Receptor-Mediated Modulation of the Interaction between Fragile X Mental Retardation Protein (FMRP) and THE Fragile X Related (FXR) Proteins FXR1P and FXR2P
D'Antoni S;Spatuzza M;Catania M V
2014
Abstract
Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by the lack 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 [1], including other RNA-binding proteins, such as the Fragile X related (FXR) proteins FXR1P and FXR2P. These two proteins are very similar to FMRP in their overall structure, being characterized by the presence of two KH, one RGG box RNA binding domain and nuclear localization and export signals (NLS and NES); however, their functions in the brain is much less characterized than FMRP. It has been proposed that the interaction between FXR1P and FMRP may change the affinity of FMRP for its target mRNAs with possible functional consequences for FMRP-mediated regulation of transport and translation [2]. Activation of group-I metabotropic glutamate (mGlu) receptors triggers the rapid translation of mRNAs, a mechanism implicated in synaptic plasticity and dysregulated in FXS [3]. To better understand the function of FXR1P and FXR2P in the brain and the link between mGlu5 receptor activation and FMRP function in the context of the multimolecular complex containing FXR proteins, we studied: i) the expression of FMRP, FXR1P and FXR2P in different brain areas during development in WT and Fmr1 KO mice; ii) the interaction between FMRP and FXR1P and FXR2P, and the possible modulation of these interactions by activation of mGlu5 receptors. FMRP, FXR1P and FXR2P exhibited a similar decrement of expression during development in different brain areas of WT and KO mice. The exposure of cortical slices (P14) to the group-I mGlu receptors agonist DHPG (100 mM) for 5 minutes reduced the reciprocal interaction of FRAX related proteins in both WT and KO mice, an effect antagonized by the mGlu5 receptor antagonist MPEP (3 mM). We are currently investigating different signal transduction pathways responsible for this mGlu5-mediated modulation of FMRP/ FXR1P/FXR2P interaction. Our data suggest that FMRP/FXR1P/FXR2P interaction plays a role during development and that the activation of mGlu5 receptors might influence the functions of FMRP and its related proteins by modulating their reciprocal interaction.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
