TY - JOUR
T1 - Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95
AU - Tsai, Nien Pei
AU - Wilkerson, Julia R.
AU - Guo, Weirui
AU - Maksimova, Marina A.
AU - Demartino, George N.
AU - Cowan, Christopher W.
AU - Huber, Kimberly M.
N1 - Funding Information:
This research was supported by grants from the National Institutes of Health NS045711, HD052731 (K.M.H.), F32HD069111 (N.-P.T.), F32HD062120 (J.R.W.) and from the Simons Foundations (K.M.H. and C.W.C.). We would also like to thank L. Ormazabal, N. Cabalo, F. Niere, K. Loerwald, T. Zang, D. Thompson, X. Li, and B. Chen for technical assistance; Dr. M. Rosen for the GST- Pcdh10 constructs; Dr. J. Gibson for helpful discussions; and Drs. Robert and Jennifer Darnell for sharing their FMRP-CLIP target list prior to publication.
PY - 2012/12/21
Y1 - 2012/12/21
N2 - The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination.
AB - The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination.
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U2 - 10.1016/j.cell.2012.11.040
DO - 10.1016/j.cell.2012.11.040
M3 - Article
C2 - 23260144
AN - SCOPUS:84871563278
SN - 0092-8674
VL - 151
SP - 1581
EP - 1594
JO - Cell
JF - Cell
IS - 7
ER -