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

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.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…However, it is clear that FMRP also binds many non-synaptic transcripts, and that translational regulation of most synaptic transcripts does not occur exclusively (or even predominantly) locally at synapses [5,12,30]. Although many mechanisms have been proposed to explain the RNA-binding specificity of FMRP, including both secondary structure (G-quartet) and consensus nucleotide sequences [34], there is little compelling evidence for any universal mechanism [35]. Therefore, it remains unclear by which mechanism(s) FMRP specifically binds target mRNAs, or which mRNAs contribute predominantly to FXS neuropathology.…”

“…When activated by MEF2, Mdm2 normally disassembles synaptic scaffolds to limit excitatory synapse number, so this defect drives FXS hyperexcitability [50]. In both Drosophila and mouse models, FMRP binds mRNA encoding bone morphogenic protein receptor type II (BMPR2) , which activates LIM-domain kinase 1 (LIMK1) to inhibit actin-binding Cofilin and cause actin reorganization that promotes synaptogenesis in the FXS condition (Table 2) [35]. Genetic or pharmacological correction of BMPR2-LIMK signaling rectifies synaptic and movement defects in the Drosophila FXS model [51].…”

“…This question is complicated by our ever-increasing grasp of mRNA complexity [11,12], as well as by examples of FMRP acting as a translational activator [55]. FMRP also has multiple mRNA-binding domains [35], but it is not clear whether they work together, separably or sequentially. Moreover, FMRP interacts with multiple other RNA-binding translational regulators [40–43], microRNA [10,42] and ribosomal components [36], highlighting unanswered questions about FMRP mechanisms of translation regulation.…”

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…In particular, Mmp hyperactivity has been causally implicated in FXS and related ASD conditions (Abdallah and Michel, 2013;Dziembowska et al, 2013;Sidhu et al, 2014;Siller and Broadie, 2011). The synaptic cytoarchitectural phenotypes of timp mutants phenocopy the Drosophila FXS model (Zhang et al, 2001), and trans-synaptic signaling defects are causative in synaptic structural and functional defects in this disease model (Friedman et al, 2013), including BMP signaling (Kashima et al, 2016). By re-creating the elevated Mmp activity characterizing neurological disease conditions such as FXS, our timp genetic tools provide insights into fundamental synaptic mechanisms with direct clinical relevance.…”

“…Importantly, Fragile X Mental Retardation Protein (FMRP) is a downstream effector of Spartin function, limiting BMP Gbb signaling (Nahm et al, 2013). Loss of FMRP causes Fragile X syndrome (FXS), and reducing non-canonical BMP signaling alleviates the synaptic defects in Drosophila and mouse FXS disease models (Kashima et al, 2016). Likewise, targeted mutation of the FXS-related S6 kinase (S6K) similarly results in both expanded synaptic architecture and decreased SV endocytosis at the Drosophila NMJ (Zhao et al, 2015), once again resembling timp null phenotypes (Figs 2 and 3).…”