Cortical wiring by synapse-specific control of local protein synthesis

Neurons use local protein synthesis as a mechanism to support their morphological complexity, which requires independent control across multiple subcellular compartments including individual synapses. However, to what extent local translation is differentially regulated at the level of specific synaptic connections remains largely unknown. Here, we identify a signaling pathway that regulates the local synthesis of proteins required for the formation of excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves the regulation of the mTORC1 inhibitor Tsc2 by the receptor tyrosine kinase ErbB4, which enables the local control of mRNA translation in a cell type-specific and synapse-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins that regulates the formation of excitatory inputs on PV+ interneurons downstream of ErbB4 signaling. Our work demonstrates that local protein translation is regulated at the level of specific connections to control synapse formation in the nervous system.

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Microglia perform local protein synthesis at perisynaptic and phagocytic structures

10.1101/2021.01.13.426577 ◽

2021 ◽

Author(s):

Michael J. Vasek ◽

Jelani D. Deajon-Jackson ◽

Yating Liu ◽

Haley W. Crosby ◽

Jiwon Yi ◽

...

Keyword(s):

Protein Synthesis ◽

De Novo ◽

Protein Translation ◽

Local Translation ◽

Slice Preparation ◽

Local Protein Synthesis ◽

Phagocytic Cups ◽

Regulate Protein ◽

Lysosomal Proteins ◽

Local Protein

AbstractRecent studies have illuminated the importance of several key signaling pathways in regulating the dynamic surveillance and phagocytic activity of microglia. Yet little is known about how these signals result in the assembly of phagolysosomal machinery near targets of phagocytosis, especially in processes distal from the microglial soma. Neurons, astrocytes, and oligodendrocytes locally regulate protein translation within distal processes. Therefore, we tested whether there is regulated local translation within peripheral microglia processes (PeMPs). We show that PeMPs contain ribosomes which engage in de novo protein synthesis, and these associate with a subpool of transcripts involved in pathogen defense, motility, and phagocytosis. Using a live slice preparation, we further show that acute translation blockade impairs the formation of PeMP phagocytic cups, the localization of lysosomal proteins within them, and phagocytosis. Collectively, these data argue for a regulated local translation in PeMPs and indicate a need for new translation to support dynamic microglial function.

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Synapse Formation and Plasticity: The Roles of Local Protein Synthesis

The Neuroscientist ◽

10.1177/1073858404274110 ◽

2005 ◽

Vol 11 (3) ◽

pp. 228-237 ◽

Cited By ~ 12

Author(s):

Ryanne Wiersma-Meems ◽

Jan Van Minnen ◽

Naweed I. Syed

Keyword(s):

Protein Synthesis ◽

Synapse Formation ◽

Local Protein Synthesis ◽

Local Protein

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Monosomes actively translate synaptic mRNAs in neuronal processes

Science ◽

10.1126/science.aay4991 ◽

2020 ◽

Vol 367 (6477) ◽

pp. eaay4991 ◽

Cited By ~ 26

Author(s):

Anne Biever ◽

Caspar Glock ◽

Georgi Tushev ◽

Elena Ciirdaeva ◽

Tamas Dalmay ◽

...

Keyword(s):

Protein Synthesis ◽

Active Sites ◽

Synaptic Proteins ◽

Messenger Rnas ◽

Local Protein Synthesis ◽

Relative Paucity ◽

Polysome Profiling ◽

Neuronal Processes ◽

Ribosome Footprinting ◽

Local Protein

To accommodate their complex morphology, neurons localize messenger RNAs (mRNAs) and ribosomes near synapses to produce proteins locally. However, a relative paucity of polysomes (considered the active sites of translation) detected in electron micrographs of neuronal processes has suggested a limited capacity for local protein synthesis. In this study, we used polysome profiling together with ribosome footprinting of microdissected rodent synaptic regions to reveal a surprisingly high number of dendritic and/or axonal transcripts preferentially associated with monosomes (single ribosomes). Furthermore, the neuronal monosomes were in the process of active protein synthesis. Most mRNAs showed a similar translational status in the cell bodies and neurites, but some transcripts exhibited differential ribosome occupancy in the compartments. Monosome-preferring transcripts often encoded high-abundance synaptic proteins. Thus, monosome translation contributes to the local neuronal proteome.

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Monosomes actively translate synaptic mRNAs in neuronal processes

10.1101/687475 ◽

2019 ◽

Author(s):

Anne Biever ◽

Caspar Glock ◽

Georgi Tushev ◽

Elena Ciirdaeva ◽

Julian D. Langer ◽

...

Keyword(s):

Protein Synthesis ◽

Active Sites ◽

Synaptic Proteins ◽

Local Protein Synthesis ◽

Relative Paucity ◽

Large Size ◽

Polysome Profiling ◽

Neuronal Processes ◽

Ribosome Footprinting ◽

Local Protein

AbstractIn order to deal with their huge volume and complex morphology, neurons localize mRNAs and ribosomes near synapses to produce proteins locally. A relative paucity of polyribosomes (considered the active sites of translation) detected in electron micrographs of neuronal processes (axons and dendrites), however, has suggested a rather limited capacity for local protein synthesis. Polysome profiling together with ribosome footprinting of microdissected synaptic regions revealed that a surprisingly high number of dendritic and/or axonal transcripts were predominantly associated with monosomes (single ribosomes). Contrary to prevailing views, the neuronal monosomes were in the process of active protein synthesis (e.g. they exhibited elongation). Most mRNAs showed a similar translational status in both compartments, but some transcripts exhibited differential ribosome occupancy in the somata and neuropil. Strikingly, monosome-preferred transcripts often encoded high-abundance synaptic proteins. This work suggests a significant contribution of monosome translation to the maintenance of the local neuronal proteome. This mode of translation can presumably solve some of restricted space issues (given the large size of polysomes) and also increase the diversity of proteins made from a limited number of ribosomes available in dendrites and axons.

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The Coordination of Local Translation, Membranous Organelle Trafficking, and Synaptic Plasticity in Neurons

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.711446 ◽

2021 ◽

Vol 9 ◽

Author(s):

Dipen Rajgor ◽

Theresa M. Welle ◽

Katharine R. Smith

Keyword(s):

Protein Synthesis ◽

Synaptic Plasticity ◽

Mrna Translation ◽

Synaptic Function ◽

Synaptic Proteins ◽

Local Translation ◽

Local Protein Synthesis ◽

Regulatory Processes ◽

Regulation Of Activity ◽

Activity Dependent

Neurons are highly complex polarized cells, displaying an extraordinary degree of spatial compartmentalization. At presynaptic and postsynaptic sites, far from the cell body, local protein synthesis is utilized to continually modify the synaptic proteome, enabling rapid changes in protein production to support synaptic function. Synapses undergo diverse forms of plasticity, resulting in long-term, persistent changes in synapse strength, which are paramount for learning, memory, and cognition. It is now well-established that local translation of numerous synaptic proteins is essential for many forms of synaptic plasticity, and much work has gone into deciphering the strategies that neurons use to regulate activity-dependent protein synthesis. Recent studies have pointed to a coordination of the local mRNA translation required for synaptic plasticity and the trafficking of membranous organelles in neurons. This includes the co-trafficking of RNAs to their site of action using endosome/lysosome “transports,” the regulation of activity-dependent translation at synapses, and the role of mitochondria in fueling synaptic translation. Here, we review our current understanding of these mechanisms that impact local translation during synaptic plasticity, providing an overview of these novel and nuanced regulatory processes involving membranous organelles in neurons.

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Faculty Opinions recommendation of Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735775241.793563562 ◽

2019 ◽

Author(s):

Sajikumar Sreedharan ◽

Radha Raghuraman

Keyword(s):

Protein Synthesis ◽

Local Protein Synthesis ◽

Local Protein

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Dendritic ribosomes suggest local protein synthesis during estrous synaptogenesis

Neuroreport ◽

10.1097/00001756-200307180-00015 ◽

2003 ◽

Vol 14 (10) ◽

pp. 1357-1360 ◽

Cited By ~ 12

Author(s):

J. Brian McCarthy ◽

Teresa A. Milner

Keyword(s):

Protein Synthesis ◽

Local Protein Synthesis ◽

Local Protein

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Protein synthesis in the dendrite

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0887 ◽

2002 ◽

Vol 357 (1420) ◽

pp. 521-529 ◽

Cited By ~ 43

Author(s):

Shao Jun Tang ◽

Erin M. Schuman

Keyword(s):

Protein Synthesis ◽

Neural Plasticity ◽

Messenger Rna ◽

Mrna Translation ◽

Synaptic Activity ◽

Synaptic Proteins ◽

Local Source ◽

Synaptic Protein ◽

Specific Proteins ◽

Molecular Nature

In neurons, many proteins that are involved in the transduction of synaptic activity and the expression of neural plasticity are specifically localized at synapses. How these proteins are targeted is not clearly understood. One mechanism is synaptic protein synthesis. According to this idea, messenger RNA (mRNA) translation from the polyribosomes that are observed at the synaptic regions provides a local source of synaptic proteins. Although an increasing number of mRNA species has been detected in the dendrite, information about the synaptic synthesis of specific proteins in a physiological context is still limited. The physiological function of synaptic synthesis of specific proteins in synaptogenesis and neural plasticity expression remains to be shown. Experiments aimed at understanding the mechanisms and functions f synaptic protein synthesis might provide important information about the molecular nature of neural plasticity.

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