Heterochronic Genes Turn Back the Clock in Old Neurons

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Science  19 Apr 2013:
Vol. 340, Issue 6130, pp. 282-283
DOI: 10.1126/science.1237921

Although some neuron types regenerate better than others, all neurons lose the ability to regenerate with age. This intrinsic decline is the primary cause of regeneration failure even in permissive environments. This was shown in 1995 by comparing the regeneration ability of retinal neurons from different aged retinas growing into tectums of different ages (1). Embryonic retinal axons regrew into tectum of any age, including older tectum with an inhibitory glial environment, whereas postnatal day 2 or older retinal axons failed to regrow even into embryonic tectum. This indicated a “programmed” loss of axon regeneration ability with neuron age. Similarly, young hindbrain neurons transplanted into older spinal cords could regenerate axons into a normally inhibitory myelinated environment (2). Despite the clear therapeutic implications of these observations, the underlying molecular mechanisms controlling age-dependent regenerative capacity were unclear. On page 372 in this issue, Zou et al. (3) report that the highly conserved let-7–LIN-41 heterochronic signaling pathway is responsible for part of the age-related decline in axon regeneration in the worm Caenorhabditis elegans.

Zou et al. examined axon regeneration in mutants of dcr-1 (dicer) and alg-1 (argonaute), which are critical for microRNA biogenesis. The authors found that alg-1 mutants showed improved axon regeneration. Out of 90 microRNAs tested, 10 that had late-onset expression correlated with the decline in axon regeneration. Only one, let-7, was affected by alg-1 and expressed in the mechanosensory anterior ventral microtubule (AVM) neuron. let-7 is a 21-nucleotide RNA that regulates the heterochronic gene lin-41 (4), which in turn inhibits the LIN-29 transcription factor (5). Heterochronic genes cause shifts in the timing of developmental events primarily through changes in the timing of mitotic-associated differentiation events (6). The let-7–LIN-41 heterochronic pathway regulates larval-toadult fate transitions (5). Zou et al. discovered that this pathway also controls the axon regeneration ability of postmitotic neurons (see the figure). In larval animals, LIN-41 inhibits LIN-29 to keep axon regeneration robust in young neurons, while at the same time repressing ALG-1 function to inhibit let-7 microRNA biogenesis. In adult animals, the signaling pathway somehow switches, possibly via a positive feedback loop between let-7 and ALG-1 (7). let-7 targets LIN-41, thus relieving inhibition of the LIN-29 transcription factor, which then targets unknown genes to repress axon regeneration in adult neurons.

Regulating neuron regeneration.

(A) Genetic pathway controlling regeneration competency. (B) LIN-41 is expressed in early larval stages, when young neurons regenerate efficiently. Onset of let-7 expression correlates with later larval and adult stages. Increasing let-7 expression in aging neurons inhibits regeneration via inhibition of LIN-41 and disinhibition of LIN-29. (C) Regeneration in older neurons can be restored by disrupting let-7 expression or increasing LIN-41 expression through adulthood.

The most surprising feature of this pathway is that transiently disrupting let-7 function at the time of axotomy in older neurons still leads to an improvement in axon regeneration. Thus, an older postmitotic neuron can be rapidly converted to a younger, more robust state. Although encouraging and relevant for the potential therapeutic application of this pathway to spinal cord injury, this is not the first finding of heterochronic genes acting cell autonomously in postmitotic neurons. LIN-14 regulates the timing of synaptic remodeling during the maturation of a specific class of motor neurons in C. elegans (8). This result is particularly interesting because LIN-14 is regulated by the lin-4 microRNA, which in turn can regulate let-7 (9). lin-4, via LIN-14, affects axon pathfinding of the AVM neuron partly by regulating the UNC-40 netrin receptor (10). ALG-1 also regulates the biogenesis of lin-4 (in addition to let-7) and shows a similar AVM axon pathfinding phenotype. Yet, the finding by Zou et al. that lin-4 shows no axon regeneration phenotype is perplexing given the pathfinding requirements for regenerating axons and the interconnected heterochronic signaling pathways.

Are there other genes that affect the agerelated decline in axon regeneration? The kinase DLK-1 has a potent effect on axon regeneration, and its overexpression rescues the age-related decline in axon regeneration ability in DD motor neurons (11). However, it is not known if there is a corresponding decline in DLK-1 activity with age. Zou et al. found that lin-41 could not suppress the DLK-1 pathway. It will be interesting to determine if these two pathways act in parallel to further delay the decline of axon regeneration. A recent screen found several genes that showed improved axon regeneration and are obvious candidates to test for their influence on its age-related decline (12).

What is the potential for this heterochronic pathway to function in humans? The LIN-41–TRIM71 regulatory circuit is present in mammals and is similarly regulated by let-7 (5, 13, 14). let-7, LIN-41, and LIN-29 are being extensively studied in mice for their role in controlling cell proliferation and differentiation (15). Just as in C. elegans, mammalian LIN-41 expression decreases with age and is associated with decreased proliferation and increased differentiation of neural tissue (13, 16). Thus, it is likely that this pathway is functioning in a similar way to inhibit axon regeneration in postmitotic mammalian neurons.

Why would older neurons decrease their ability to regenerate axons? In C. elegans, the steep decline in axon regeneration ability is associated with a cessation of body growth and the beginning of reproduction. Perhaps there is a diversion of energy toward reproduction or an advantage to stabilizing basic neural circuits. In the mammalian central nervous system, the initial loss of axon regeneration ability occurs very early in development and suggests that axon stabilization may be the more likely rationale. The reason will remain a mystery until more of the genes regulating the age-dependent decline in axon regeneration are identified and their functions in aging neurons understood. Zou et al. have taken an important first step toward understanding aging neurons with the identification of the heterochronic let-7–LIN-41 pathway in C. elegans.



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