RESUMO
In neuronal development, dynamic rearrangement of actin promotes axonal growth cone extension, and spatiotemporal translation of local mRNAs in response to guidance cues directs axonal growth cone steering, where cofilin plays a critical role. While regulation of cofilin activity is well studied, regulatory mechanism for cofilin mRNA translation in neurons is unknown. In eukaryotic cells, proteins can be synthesized by cap-dependent or cap-independent mechanism via internal ribosome entry site (IRES)-mediated translation. IRES-mediated translation has been reported in various pathophysiological conditions, but its role in normal physiological environment is poorly understood. Here, we report that 5'UTR of cofilin mRNA contains an IRES element, and cofilin is predominantly translated by IRES-mediated mechanism in neurons. Furthermore, we show that IRES-mediated translation of cofilin is required for both axon extension and axonal growth cone steering. Our results provide new insights into the function of IRES-mediated translation in neuronal development.
Assuntos
Axônios/fisiologia , Cofilina 1/genética , Cones de Crescimento/fisiologia , Sítios Internos de Entrada Ribossomal/genética , Neurogênese/genética , Regiões 5' não Traduzidas/genética , Animais , Encéfalo/embriologia , Sistemas CRISPR-Cas , Linhagem Celular , Proliferação de Células/genética , Cofilina 1/metabolismo , Camundongos , Biossíntese de Proteínas/genética , RNA Mensageiro/genéticaRESUMO
Local translation of synaptic mRNAs is an important process related to key aspects of central nervous system development and physiology, including dendritogenesis, axonal growth cone morphology and guidance and synaptic plasticity. Accordingly, local translation is compromised in several intellectual disabilities, including Fragile X syndrome, tuberous sclerosis and Down syndrome. Down Syndrome Cell Adhesion Molecule (DSCAM) is a gene with ascribed functions in neuronal wiring that belongs to the Down Syndrome Critical Region (DSCR) of chromosome 21. In this review, we discuss the evidence for local translation of the DSCAM mRNA in dendrites and axonal growth cones of mouse hippocampal neurons, as well as the possible functions of the locally translated DSCAM protein.
Assuntos
Moléculas de Adesão Celular/metabolismo , Dendritos/metabolismo , Síndrome de Down/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Animais , Cones de Crescimento/metabolismo , Humanos , Camundongos , Biossíntese de Proteínas/fisiologiaRESUMO
Developmental changes in the expression and localization of drebrin has been mainly analyzed in chick embryo and young rat by various anti-drebrin polyclonal and monoclonal antibodies. Immunoblot analysis demonstrated that the adult drebrin isoform (drebrin A) is restricted to neural tissues, while the embryonic drebrin isoforms (drebrin E1 and E2 in chicken and drebrin E in mammals) are found in a wide variety of tissues. In the developing brain, drebrin E (including chicken drebrin E2) is expressed in newly generated neurons. During neuronal migration, drebrin E is distributed ubiquitously within the neurons. Once drebrin A is expressed in the developing neuron, drebrin E is no longer present within the cell soma and accumulates in the growth cone of growing processes, resulting in the cessation of neuronal migration. The limited subcellular localization of drebrin A, which is possibly regulated by a drebrin A-specific mechanism, is likely to affect the localization of drebrin E. In the adult brain, drebrin is mainly localized in dendritic spines, but in some nuclei, drebrin can be detected in neuronal somata as well as dendritic spines. The fact that the developmental changes in drebrin expression highly correlate in time with the sensitive period of visual cortical plasticity in kittens suggests that synaptic plasticity depends on drebrin.