Axon outgrowth and neuronal differentiation defects after a-SMN and FL-SMN silencing in primary hippocampal cultures
Autor: | Francesca Colciaghi, Denise Locatelli, Daniela Rita Pletto, Adele Finardi, Giorgio Battaglia, Paola Nobili, Cinzia Cagnoli, Silvia Capra |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Neurite Cellular differentiation animal diseases Neuronal Outgrowth lcsh:Medicine SMN1 Biology Hippocampus 03 medical and health sciences 0302 clinical medicine medicine Animals Homeostasis Gene Silencing Axon lcsh:Science Neurons Multidisciplinary lcsh:R Survival of motor neuron Cell Differentiation Spinal muscular atrophy Dendrites medicine.disease SMA Survival of Motor Neuron 1 Protein Cell biology Rats nervous system diseases 030104 developmental biology medicine.anatomical_structure Phenotype nervous system Axoplasmic transport lcsh:Q 030217 neurology & neurosurgery |
Zdroj: | PLoS ONE, Vol 13, Iss 6, p e0199105 (2018) |
ISSN: | 1932-6203 |
Popis: | Spinal Muscular Atrophy (SMA) is a severe autosomal recessive disease characterized by selective motor neuron degeneration, caused by disruptions of the Survival of Motor Neuron 1 (Smn1) gene. The main product of SMN1 is the full-length SMN protein (FL-SMN), that plays an established role in mRNA splicing. FL-SMN is also involved in neurite outgrowth and axonal transport. A shorter SMN isoform, axonal-SMN or a-SMN, displays a more specific axonal localization and has remarkable axonogenic properties in NSC-34. Introduction of known SMA mutations into the a-SMN transcript leads to impairment of axon growth and morphological defects similar to those observed in SMA patients and animal models. Although there is increasing evidence for the relevance of SMN axonal functions in SMA pathogenesis, the specific contributions of FL-SMN and a-SMN are not known yet. This work aimed to analyze the differential roles of FL-SMN and a-SMN in axon outgrowth and in neuronal homeostasis during differentiation of neurons into a mature phenotype. We employed primary cultures of hippocampal neurons as a well-defined model of polarization and differentiation. By analyzing subcellular localization, we showed that a-SMN is preferentially localized in the growing axonal compartment. By specifically silencing FL-SMN or a-SMN proteins, we demonstrated that both proteins play a role in axon growth, as their selective down-regulation reduces axon length without affecting dendritic arborization. a-SMN silencing, and in minor extent FL-SMN silencing, resulted in the growth of multi-neuritic neurons, impaired in the differentiation process of selecting a single axon out of multiple neurites. In these neurons, neurites often display mixed axonal and dendritic markers and abnormal distribution of the axonal initial segment protein Ankirin G, suggesting loss of neuronal polarity. Our results indicate that a-SMN and FL-SMN are needed for neuronal polarization and organization of axonal and dendritic compartments, processes that are fundamental for neuronal function and survival. |
Databáze: | OpenAIRE |
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