Research ArticleNeuroscience

Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome

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Sci. Signal.  07 Jun 2016:
Vol. 9, Issue 431, pp. ra58
DOI: 10.1126/scisignal.aaf6060

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BMP signaling underlies fragile X syndrome

Fragile X syndrome (FXS) is a heritable cognitive disability and autism spectrum disorder caused by loss of expression of the gene encoding the RNA binding protein FMRP. FMRP suppresses the translation of various mRNAs. Kashima et al. found that the transcript encoding the bone morphogenetic protein type II receptor (BMPR2) was a critical FMRP target that contributed to the neuronal morphology seen in FXS. Loss of FMRP in fruitfly and mice increased the abundance of BMPR2 and activated a downstream kinase LIMK1 in neurons; increased BMPR2 abundance and cofilin phosphorylation (suggesting increased LIMK1 activity) were also detected in postmortem brain tissue from FXS patients. Reducing signaling through the BMPR2-LIMK1 pathway suppressed abnormal dendritic spine growth in FXS model mice, suggesting that this might be a therapeutic option for FXS patients.

Abstract

Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.

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