Abstract
Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons by predominant retrograde transport However, on overexpression rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration.
Highlights
Axon regeneration fails in the adult mammalian CNS due to a combination of extrinsic inhibitory cues and an inadequate intrinsic regenerative response (Fawcett et al, 2012; Liu et al, 2011)
Dissociated embryonic day 18 (E18) rat cortical neurons were grown in the presence of astrocyte feeder cultures (Kaech and Banker, 2006)
We focused on rab11 because it is associated with the recycling endosomes responsible for bringing growth receptors and integrins into axons, and because these endosomes are reported to be restricted to a somatodendritic distribution in-vivo (Sheehan et al, 1996; Eva et al, 2010; 2012)
Summary
Axon regeneration fails in the adult mammalian CNS due to a combination of extrinsic inhibitory cues and an inadequate intrinsic regenerative response (Fawcett et al, 2012; Liu et al, 2011). Long-distance regeneration can only be achieved if axons have a high intrinsic growth ability (Liu et al, 2010; Cheah et al, 2016) Embryonic axons have this ability, and can elongate for long distances if immature neurons are transplanted into the adult CNS environment (Lu et al, 2012; Reier et al, 1986). Several changes occur during neuronal differentiation that might explain this maturational reduction in growth ability Amongst these a key factor that changes radically with maturity is the establishment of selective transport to axons and dendrites (Bentley and Banker, 2016; Britt et al, 2016; Franssen et al, 2015; Maeder et al, 2014; Petersen et al, 2014).
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