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Stored mRNAs in Brain Cells
One of the most important areas of local translational regulation may be in the brain. The storage of long-term memory requires new protein synthesis, and the local translation of mRNAs in the dendrites of brain neurons has been proposed as a control point for increasing the strength of synaptic connections (Martin 2000; Klann et al. 2004; Wang and Tiedge 2004). The ability to increase the strength of the connections between neurons is critical in forming the original architecture of the brain and also in the ability to learn. Indeed, in recent studies of mice, Kelleher and colleagues (2004) have shown that neuronal activity-dependent memory storage depends on the activation of eIF4E and other components of protein synthesis.
Several mRNAs appear to be transported along the cytoskeleton to the dendrites of neurons (the “receiving portion” of the neuron, where synapse connections are formed with the other neurons). These messages include those mRNAs encoding receptors for neurotransmitters (needed to transmit the signals from one neuron to another); activity-regulated enzymes; and the cytoskeletal components needed to build a synapse (Figure 1). As we will see in later chapters of the textbook, one of the proteins responsible for constructing specific synapses is brain-derived neurotrophic factor, or BDNF. BDNF regulates neural activity and appears to be critical for new synapse formation. Takei and colleagues (2004) have shown that BDNF induces local translation of these neural messages in the dendrites.
Another indication of the importance of dendritic mRNA translation comes from studies of a leading cause of human mental retardation, fragile X syndrome. Fragile X syndrome is caused by loss-of-function mutations in the X-linked FMR1 gene. The FMR1 protein (FMRP) appears to prevent the translation of several mRNAs that are being transported to the dendrites along microtubules in response to stimulation by glutamic acid (Dictenberg et al. 2008; Wang et al. 2008b). In the absence of functional FMRP, these mRNAs are expressed in the wrong amounts, leading to signaling abnormalities that are believed to cause the problems in cognition and learning. Indeed, a subset of the mRNAs regulated by FMRP have been linked to autism and new synapse formation, and autism is often seen in patients with Fragile X syndrome (Darnell et al. 2011; Darnell and Richter 2013) Thus, translational regulation in neurons might be important not only for their initial development but also for their continued ability to learn and change.
Darnell J. C., and Richter J. D. 2012. Cytoplasmic RNA-binding proteins and the control of complex brain function. Cold Spring Harb Perspect Biol. 4(8):a012344.
Darnell J. C., Van Driesche S. J., Zhang C., Hung K. Y., Mele A., Fraser C. E., Stone E. F., Chen C,. Fak J. J., Chi S. W., Licatalosi D. D., Richter J. D., and Darnell R. B. 2011. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146: 247–261.
Dictenberg, J. B., Swanger, S. A. Antar, L. N. Singer R. H. and Bassell G. J. 2008. A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev. Cell 14: 926–939.
Kelleher R. J. III, Govidarajan, A, .Jung, H.-Y., Kang, H. and Tonegawa. S. 2004. The translational control of MAPK signaling in long-term synaptic plasticity and memory. Cell 116: 467–479.
Klann, E., Antion, M. D., Banko J. L, and Hou. L. 2004. Synaptic plasticity and translation initiation. Learning Memory 11: 365–372.
Martin, K. C., Barad, M., and Kandel, E. R. 2000. Local protein synthesis and its role in synapse-specific plasticity. Curr. Opin. Neurobiol. 10: 587–592.
Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., and Nawa, H. 2004. Brain-derived neurotrophic factor induces mammalian target of Rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 24: 9760–9769.
Wang, H. and Tiedge, H. 2004. Translational control at the synapse. Neuroscientist 10:456–466.
Wang, H., Wu, L. J., Zhang F., and Zhuo, M. 2008. Roles of calcium-stimulated adenylyl cyclase and calmodulin-dependent protein kinase IV in the regulation of FMRP by group I metabotropic glutamate receptors. J. Neurosci. 28: 4385–4397.
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