FMRP regulation of aggrecan mRNA translation controls perineuronal net development

Fragile X Messenger Ribonucleoprotein (FMRP) regulates translational efficiency of aggrecan mRNA through the protection of its poly(A) tail. Loss of FMRP leads to a reduction of aggrecan mRNA poly(A) tail length, which decreases the number of ribosomes that bind the mRNA to initiate translation. The reduction in Aggrecan protein levels results in a delay in formation of perineuronal nets (PNNs). PNNs are necessary for the excitatory/inhibitory (E/I) balance in the brain, which is disrupted in mouse models of Fragile X Syndrome (FXS), a neurodevelopmental disorder caused by the loss of FMRP. AbstractPerineuronal nets (PNNs) are mesh-like structures on the surfaces of parvalbumin-expressing inhibitory and other neurons, and consist of proteoglycans such as aggrecan, brevican, and neurocan. PNNs regulate the Excitatory/Inhibitory (E/I) balance in the brain and are formed at the closure of critical periods of plasticity during development. PNN formation is disrupted in Fragile X Syndrome, which is caused by silencing of the fragile X messenger ribonucleoprotein 1 (Fmr1) gene and loss of its protein product FMRP. FXS is characterized by impaired synaptic plasticity resulting in neuronal hyperexcitability and E/I imbalance. Here, we investigate how PNN formation is altered in FXS. PNNs are reduced inFmr1 KO mouse brain when examined by staining for the lectinWisteria floribunda agglutin (WFA) and aggrecan. Examination of PNNs by WFA staining at P14 and P42 in the hippocampus, somat...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research