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

Risa Kashima, Sougata Roy, Manuel Ascano, Veronica Martinez-Cerdeno, Jeanelle Ariza-Torres, Sunghwan Kim, Justin Louie, Yao Lu, Patricio Leyton, Kenneth D. Bloch, Thomas B. Kornberg, Paul J Hagerman, Randi J Hagerman, Giorgio Lagna, Akiko Hata

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberra58
JournalScience Signaling
Volume9
Issue number431
DOIs
StatePublished - Jun 7 2016

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Type II Bone Morphogenetic Protein Receptors
Fragile X Syndrome
Lim Kinases
Phosphotransferases
Signal transduction
Intellectual Disability
Autistic Disorder
Synapses
RNA-Binding Proteins
Signal Transduction
Neurons
Actins
Brain
Dendritic Spines
Protein Isoforms
Tissue
Prefrontal Cortex
Epigenomics
Messenger RNA
Drosophila

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. / Kashima, Risa; Roy, Sougata; Ascano, Manuel; Martinez-Cerdeno, Veronica; Ariza-Torres, Jeanelle; Kim, Sunghwan; Louie, Justin; Lu, Yao; Leyton, Patricio; Bloch, Kenneth D.; Kornberg, Thomas B.; Hagerman, Paul J; Hagerman, Randi J; Lagna, Giorgio; Hata, Akiko.

In: Science Signaling, Vol. 9, No. 431, ra58, 07.06.2016.

Research output: Contribution to journalArticle

Kashima, R, Roy, S, Ascano, M, Martinez-Cerdeno, V, Ariza-Torres, J, Kim, S, Louie, J, Lu, Y, Leyton, P, Bloch, KD, Kornberg, TB, Hagerman, PJ, Hagerman, RJ, Lagna, G & Hata, A 2016, 'Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome', Science Signaling, vol. 9, no. 431, ra58. https://doi.org/10.1126/scisignal.aaf6060
Kashima, Risa ; Roy, Sougata ; Ascano, Manuel ; Martinez-Cerdeno, Veronica ; Ariza-Torres, Jeanelle ; Kim, Sunghwan ; Louie, Justin ; Lu, Yao ; Leyton, Patricio ; Bloch, Kenneth D. ; Kornberg, Thomas B. ; Hagerman, Paul J ; Hagerman, Randi J ; Lagna, Giorgio ; Hata, Akiko. / Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. In: Science Signaling. 2016 ; Vol. 9, No. 431.
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