Let-7 and the Age-Related Decline of Neural Regeneration

The microRNA let-7 has been shown to be involved in maintenance of stem cell populations. It was mentioned in research in flies from last year: let-7 levels rise with aging, causing other changes in various proteins which result in a reduced number of stem cells that are active and maintaining tissues. Here researchers investigate let-7 in nematode worms in connection with the regenerative capacity of nerve tissue:

Like mammalian neurons, C. elegans neurons lose regeneration ability as they age, but it is not known why. C. elegans is a soil worm with its brain wiring diagram being mapped entirely - every connection between every nerve cell. Forty percent of genes identified in the worm genome have a counterpart in humans. Genes that allow neurons to connect with each other to form functional neuronal circuits and to regenerate themselves after injury are highly similar between worms and humans. Thus, what we learn in worms will likely be relevant to the development and regeneration of the human nervous system. The let-7 microRNA and its target, the LIN-41 tripartite motif protein, were recently shown to function as neuronal timers in worms to time the decline of the ability of neurons to regenerate as they age

Since let-7 and lin-41 genes are broadly expressed in different types of neurons, their roles in neuronal regeneration may be widespread. In addition to let-7, many microRNAs are also expressed in postmitotic neurons, raising the possibility that other microRNAs could also contribute to developmental decline in neuronal regeneration. In C. elegans, many aged neurons display a further decline in axon regeneration. In [at least some] aged neurons, a reduced let-7 remains able to enhance axon regeneration so it is likely that let-7 continues to contribute to the further decline in axon regeneration in aged neurons.

These discoveries have important implications in treating brain and spinal cord injury or neuro-degenerative diseases as they show that it may be possible to improve the ability of neurons in the adult brain to regenerate after injury through therapeutic inhibition of the let-7 microRNA, and thereby restore their youthful regenerative capacity. The idea of slowing down neuronal aging to promote axon regeneration after injury is an appealing possibility.

Link: http://www.impactaging.com/papers/v5/n7/full/100574.html


I have some trouble just understanding why such a mechanism would be conserved across the vast phylogenetic gap between nematodes and insects. Often cancer is invoked as a reason why selection would reduce stem-cell activity with age — to compensate for damage. Do these tiny creatures really have such a cancer problem? What other reason could be so important that this mechanism for putting the breaks on stem cells survives for hundreds of millions of years against genetic drift? Maybe it serves a role in development, then during the healthy lifespan of the organism there is a steady state level of the substance but a deteriorating micro-environment disrupts its equilibrium. That would at least explain why it exists at all.

Posted by: José at July 21st, 2013 11:12 PM

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