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Joel D. Richter, Ph.D.

Professor of Molecular Medicine

Arthur F. Koskinas Professor of Neuroscience

Program Director, Center for Collaborative Research in Fragile X

 

What we do...

We study the molecular biology of mRNA translational control by cytoplasmic polyadenylation and how this process regulates neuronal synaptic plasticity, learning, and memory.  We investigate how neurologic diseases such as Fragile X and other autism spectrum disorders (ASDs) are regulated at the translational level.           

Translational control by 3’ end formation

Many inactive mRNAs have short poly(A) tails and only when the tails are elongated does translation ensue. A key factor that regulates polyadenylation-induced translation is the RNA binding protein CPEB (Cytoplasmic Polyadenylation Element Binding Protein). CPEB binds specific 3’UTR cis elements in mRNAs and recruits unusual poly(A) polymerases and translation factors that extend poly(A) tails in the cytoplasm and promote translation.

Synaptic plasticity and learning and memory

CPEB and the cytoplasmic polyadenylation complex reside at postsynaptic sites of neurons in the mammalian central nervous system. In dendrites, this complex controls local mRNA polyadenylation-induced translation in response to synaptic stimulation. Synaptic plasticity, the ability of synapses to undergo long-lasting biochemical and morphological changes in response to stimulation, forms the underlying basis of learning and memory. CPEB knockout mice are defective for synaptic plasticity and hippocampal-dependent memory formation. Hippocampal neurons depleted of other components of the cytoplasmic polyadenylation complex with lentivirus-based shRNAs also display defects in synaptic plasticity, indicating that polyadenylation-induced translation forms an essential mechanism to control translation and higher cognitive function.

Neurons derived from CPEB knockout mice have alterations in metabolism in that ATP production by mitochondria is compromised. This deficit in ATP reduces dendrite arborization and is observed in both neurons cultured in vitro and neurons expressing an shRNA for CPEB in vivo.

Oligo (dT) fluorescent in situ hybridization (FISH) of a cultured hippocampal neuron showing an increase in dendrite polyadenylation in response to synaptic stimulation. 

Neurologic disease

The Fragile X Syndrome (FXS) is the most common heritable form of mental retardation and the most common monogenic cause of autism. FXS results from a CGG expansion in and transcriptional silencing of the FMR1 gene. FMR1 encodes FMRP, an RNA binding protein that normally represses translation in the brain. In the absence of FMRP, aberrantly high translation likely causes FXS in both humans and a mouse model. Restoration of normal translation occurs in FMRP/CPEB double knockout mice. Moreover, rescue of synapse function and learning and memory also occurs in FMRP/CPEB double knockout mice, suggesting that CPEB might be a novel therapeutic to reverse FXS.  Rescue of FXS in double knockout mice may involve altered rates of ribosome translocation on mRNA (i.e., polypeptide elongation).  Deciphering which mRNAs are loaded with ribosomes that travel at different rates is daunting, but whole genome ribosome profiling and RNA-seq may shed light on this process.

 

 Aberrant nest building in Fmr1 knockout mice (compare to wild type) is rescued in Fmr1/CPEB double knockout mice.

 

Ribosome profiling and RNA-seq of shank1 mRNA from mouse brain.

 

Elevated ribosome translocation speed in in Fmr1 knockout mouse brain (compared to WT) is rescued to normal levels in the Fmr1/CPEB double knockout brain.  Ribosome translocation speed was measured in brain lysates derived from wild type, Fmr1 KO, CPEB KO, and Fmr1/CPEB double KO mice supplemented with 35S-methionine/cysteine and hippuristanol, which inhibits initiation.

Reduced axon branching in the phrenic nerve of a CPEB4 gene trap mouse (CPEB4GT/GT) compared to wild type (CPEB4+/+).  Data from embryonic day 14.5 and 18.5 are shown.

 

 

 


One or more keywords matched the following items that are connected to Richter, Joel

Item TypeName
Academic Article Development. The message is in the translation.
Academic Article Translational control of the embryonic cell cycle.
Academic Article Dissolution of the maskin-eIF4E complex by cytoplasmic polyadenylation and poly(A)-binding protein controls cyclin B1 mRNA translation and oocyte maturation.
Academic Article Regulated CPEB phosphorylation during meiotic progression suggests a mechanism for temporal control of maternal mRNA translation.
Academic Article Regulation of local mRNA translation.
Academic Article Differential phosphorylation controls Maskin association with eukaryotic translation initiation factor 4E and localization on the mitotic apparatus.
Academic Article Amyloid precursor proteins anchor CPEB to membranes and promote polyadenylation-induced translation.
Academic Article Regulated Pumilio-2 binding controls RINGO/Spy mRNA translation and CPEB activation.
Academic Article Control of cellular senescence by CPEB.
Academic Article Human let-7a miRNA blocks protein production on actively translating polyribosomes.
Academic Article Translational unmasking of Emi2 directs cytostatic factor arrest in meiosis II.
Academic Article CPEB: a life in translation.
Academic Article Think globally, translate locally: what mitotic spindles and neuronal synapses have in common.
Academic Article RINGO/cdk1 and CPEB mediate poly(A) tail stabilization and translational regulation by ePAB.
Academic Article Think you know how miRNAs work? Think again.
Academic Article The nuclear experience of CPEB: implications for RNA processing and translational control.
Academic Article Translational regulatory mechanisms in synaptic plasticity and memory storage.
Academic Article Differential mRNA translation and meiotic progression require Cdc2-mediated CPEB destruction.
Academic Article Translational control of synaptic plasticity.
Academic Article N-methyl-D-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA polyadenylation at synapses.
Academic Article Local RNA translation at the synapse and in disease.
Academic Article Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance.
Academic Article Cytoplasmic RNA-binding proteins and the control of complex brain function.
Academic Article Selective translation of mRNAs at synapses.
Academic Article Translational control of mitochondrial energy production mediates neuron morphogenesis.
Academic Article Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.
Academic Article Progesterone and insulin stimulation of CPEB-dependent polyadenylation is regulated by Aurora A and glycogen synthase kinase-3.
Academic Article Regulation of cap-dependent translation by eIF4E inhibitory proteins.
Academic Article Reduced extinction of hippocampal-dependent memories in CPEB knockout mice.
Academic Article Translational control by neuroguidin, a eukaryotic initiation factor 4E and CPEB binding protein.
Academic Article CPEB3 and CPEB4 in neurons: analysis of RNA-binding specificity and translational control of AMPA receptor GluR2 mRNA.
Academic Article CPEB controls oocyte growth and follicle development in the mouse.
Academic Article CDK1 and calcineurin regulate Maskin association with eIF4E and translational control of cell cycle progression.
Academic Article Synapses go nucle(ol)ar.
Academic Article Analysis of mRNA translation in cultured hippocampal neurons.
Academic Article Breaking the code of polyadenylation-induced translation.
Academic Article A molecular circuit composed of CPEB-1 and c-Jun controls growth hormone-mediated synaptic plasticity in the mouse hippocampus.
Academic Article Making synaptic plasticity and memory last: mechanisms of translational regulation.
Academic Article Cytoplasmic polyadenylation and cytoplasmic polyadenylation element-dependent mRNA regulation are involved in Xenopus retinal axon development.
Academic Article Translational control from head to tail.
Academic Article Pumilio 2 controls translation by competing with eIF4E for 7-methyl guanosine cap recognition.
Academic Article CPEB4 is a cell survival protein retained in the nucleus upon ischemia or endoplasmic reticulum calcium depletion.
Academic Article CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation.
Academic Article CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence.
Academic Article Translational control in oocyte development.
Academic Article FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.
Academic Article CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity.
Academic Article Transient CPEB dimerization and translational control.
Academic Article Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.
Academic Article Translational control of cell growth and malignancy by the CPEBs.
Academic Article Dendritic GluN2A synthesis mediates activity-induced NMDA receptor insertion.
Concept Protein Binding
Concept Protein Transport
Concept Amyloid beta-Protein Precursor
Concept Fragile X Mental Retardation Protein
Concept Tumor Suppressor Protein p14ARF
Concept Tumor Suppressor Protein p53
Concept Calcium-Calmodulin-Dependent Protein Kinases
Concept Ribosomal Protein S6 Kinases, 70-kDa
Concept Protein Biosynthesis
Concept CDC2 Protein Kinase
Concept Protein Kinases
Concept Staphylococcal Protein A
Concept Protein-Serine-Threonine Kinases
Concept Protein Synthesis Inhibitors
Concept Bone Morphogenetic Protein 15
Concept Protein Multimerization
Concept Protein Stability
Concept Calcium-Calmodulin-Dependent Protein Kinase Type 2
Concept Protein Isoforms
Concept Protein Array Analysis
Academic Article Cytoplasmic polyadenylation element binding proteins in development, health, and disease.
Academic Article Dysregulation and restoration of translational homeostasis in fragile X syndrome.
Academic Article A role for the cytoplasmic polyadenylation element in NMDA receptor-regulated mRNA translation in neurons.
Academic Article Molecular mechanisms for activity-regulated protein synthesis in the synapto-dendritic compartment.

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