Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome.
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.
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Risa
R
Kashima
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Sougata
S
Roy
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Manuel
M
Ascano
Institute for Pediatric Regenerative Medicine, Department of Pathology, University of California, Davis, Davis, CA 95817, USA. MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA 95817, USA.
Veronica
V
Martinez-Cerdeno
Institute for Pediatric Regenerative Medicine, Department of Pathology, University of California, Davis, Davis, CA 95817, USA.
Jeanelle
J
Ariza-Torres
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Sunghwan
S
Kim
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Justin
J
Louie
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Yao
Y
Lu
Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
Patricio
P
Leyton
Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
Kenneth D
KD
Bloch
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Thomas B
TB
Kornberg
Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA 95817, USA.
Paul J
PJ
Hagerman
MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA 95817, USA.
Randi
R
Hagerman
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Giorgio
G
Lagna
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. akiko.hata@ucsf.edu.
Akiko
A
Hata
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D051338:Cofilin 1 / Q000378:metabolism; D003433:Crosses, Genetic; D004331:Drosophila melanogaster; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
C495811:Cfl1 protein, mouse; D051338:Cofilin 1; D034741:RNA, Small Interfering; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II