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Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth, and axon targeting?

ABSTRACT: The highly polarized architecture of neurons is important for their function. Experimental data based on dominant-negative approaches suggest that the tumor suppressor adenomatous polyposis coli (APC), a regulator of Wnt signaling and the cytoskeleton, regulates polarity of neuroectodermal precursors and neurons, helping specify one neurite as the axon, promoting its outgrowth, and guiding axon pathfinding. However, such dominant-negative approaches might affect processes in which APC is not essential. We completely removed both APCs from Drosophila melanogaster larval neural precursors and neurons, testing whether APCs play universal roles in neuronal polarity. Surprisingly, APCs are not essential for asymmetric cell division or the stereotyped division axis of central brain (CB) neuroblasts, although they do affect cell cycle progression and spindle architecture. Likewise, CB, lobular plug, and mushroom body neurons do not require APCs for polarization, axon outgrowth, or, in the latter two cases, axon targeting. These data suggest that proposed cytoskeletal roles for APCs in mammals should be reassessed using loss of function tools.

SUBMITTER: Rusan NM

PROVIDER: S-EPMC2568018 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth, and axon targeting?

Rusan Nasser M NM Akong Kathryn K Peifer Mark M

The Journal of cell biology 20081013 2

The highly polarized architecture of neurons is important for their function. Experimental data based on dominant-negative approaches suggest that the tumor suppressor adenomatous polyposis coli (APC), a regulator of Wnt signaling and the cytoskeleton, regulates polarity of neuroectodermal precursors and neurons, helping specify one neurite as the axon, promoting its outgrowth, and guiding axon pathfinding. However, such dominant-negative approaches might affect processes in which APC is not ess ...[more]

PMID: 18852302

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Project description: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.

Dataset Information

Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth, and axon targeting?

Publications

Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth, and axon targeting?

Similar Datasets

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