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neuronal growth

Tuesday 24 August 2004

Pathogenesis

- Once neurons have reached their correct destination, they need to extend axons and dendrites. Evidence is emerging that highlights the importance of the centrosome during axonal elongation and targeting.

Once neuronal cell bodies have reached their final position, the centrosome seems to be crucial for organizing the cytoskeleton for axonal elongation and particle transport. For example, axonal growth depends on microtubule nucleation at the centrosome and the translocation of microtubules that are released from the centrosome into the axon in a dynein-dependent manner. This view is supported by the negative effect of overexpression of dynamitin (which inhibits dynein function) on the outgrowth of axons in neurons in culture.

- In hereditary spastic paraplegia (HSP), the axons that comprise the corticospinal tracts progressively degenerate, usually starting in early adulthood, which results in progressive spasticity and weakness of the lower extremities.

Although several HSP genes have been cloned so far, SPG4, which encodes the protein spastin, seems to be the most common causative gene in autosomal-dominant cases.

Spastin is a member of the AAA FAMILY of proteins and belongs to the same subfamily as p60 katanin, a protein that severs and releases microtubules from the centrosome during axonal growth, thereby allowing the microtubules to move into the growing axon.

Spastin localizes to spindle poles, midbodies and distal portions of axons, as well as to branching points. Furthermore, spastin has a role in regulating microtubule stability, and in Drosophila melanogaster it affects synaptic plasticity and neurotransmission. Importantly, spastin interacts with the centrosomal protein NA14, both in a yeast two-hybrid screen and in mammalian cells, as shown by co-immunoprecipitation studies, and is enriched in centrosomal fractions from HeLa CELLS.

These data indicate that spastin affects the axonemal microtubule backbone and regulates microtubules in the cellular locations in which dynamic cytoskeletal remodelling occurs.

Interestingly, the human NA14 protein and its Chlamydomonas reinhardtii orthologue DIP13 localize to similar locations in the two organisms: to the basal bodies and flagellar axonemes in the green algae, and to the basal bodies, flagella and centrosome in human sperm and HeLa cells, respectively.

This highlights the similarities between the mechanisms of growth and transport along, flagella, cilia and axons, all of which depend on microtubule-based architecture and transport.

Supporting this idea, evidence indicates that the intraflagellar-transport (IFT) molecular-motor kinesin might have a role in axonal transport by moving vesicles from the neuronal cell body to the tip of the axon.

In this context, the centrosome has a role not only as an MTOC in the realm of spindle formation and cell division but also to potentially facilitate or regulate transport in post mitotic cells, such as neurons, where active transport is crucial due to the long distances spanned by these cells (up to 1m in humans).

References

- Henley J, Poo MM. Guiding neuronal growth cones using Ca2+ signals. Trends Cell Biol. 2004 Jun;14(6):320-30. PMID: 15183189