Thursday, April 4, 2013

Neurons and New Newt Legs

Salamanders are amazing and mystical creatures.
Salamanders and their amazing leg-growing superpower (source)
Not because they can survive in fire (they can't), but because they can regrow amputated limbs.
A paper in 2007 investigates exactly what neural signals are required for this amazing superpower.

Newt Amputee (Kumar et al., 2007)
This paper brings together two interesting things about salamander (newt) leg growth.

1. The salamander arm 'knows' where it was cut. If it is cut at the wrist it only grows a hand (paw?...foot?), if it is cut at the shoulder, it grows the whole leg/arm. So one question is HOW does the arm know?

The answer is surprisingly simple: there is a small protein called Prod 1 that is highly concentrated at the shoulder and progressively decreases along the arm. This protein could tell the new bud of growing cells where it is, and what it should grow into.


2. To regenerate, the arm needs intact nerve endings at the point of the cut. That is, the nerve fiber that goes down the arm has to be attached to the nervous system. If the nerve is cut further up than the arm cut, the arm will not regenerate.

Kumar et al., 2007 Author Summary Figure
Kumar et al. (2007) found a molecule that ties these two interesting things together, completing the newt leg regeneration story. They find a molecule, nAG (n for newt and AG for anterior gradient) which binds to Prod 1, and is secreted by the nerve sheath (the Schwann cells that surrounds nerve fibers).

They show that when they cut the nerve further up the arm (denervation), they don't get nAG expression and they don't get limb regeneration. But, when they artificially supply nAG, (see D and E above), the amputated and denervated limb starts to grow. 

This is a really neat 'rescue experiment' suggesting that the reason the nerve is necessary for regeneration is because it triggers nAG release which binds to Prod 1 and says "GROW".

One thing that they don't do (because genetically manipulating salamanders is not really a thing yet) is remove nAG, but keep the nerve intact. This would show that the only important thing the nerve fiber is doing is triggering nAG.

This study is also a small step towards limb regeneration in humans, not because injecting nAG into an amputated human limb could regenerate it (It couldn't), but because the more we understand about how the system works, the more likely we can figure out a way to engineer a similar system in humans. 

© TheCellularScale
Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, & Brockes JP (2007). Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science (New York, N.Y.), 318 (5851), 772-7 PMID: 17975060

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