The Heterochronic Gene lin-14 Controls Axonal Degeneration in C. elegans Neurons

Ritchie, Fiona K.; Knable, Rhianna; Chaplin, Justin; Gursanscky, Rhiannon; Gallegos, Maria; Neumann, Brent; Hilliard, Massimo A.

doi:10.1016/j.celrep.2017.08.083

Cited by 9 publications

(5 citation statements)

References 67 publications

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“…In mutants where attachment pathways are completely disrupted, the PLM axon fails to become ensheathed within the epidermis and instead resides between the muscle and epidermis where it originally develops 11 . We have previously shown that preventing attachment and ensheathing of the PLM axon within the epidermis is not sufficient to cause axonal degeneration 44 . A potential explanation for these seemingly contradictory phenotypes is that in the case of uniform attachment (or uniform detachment) of the axon and epidermis, the axon is able to withstand compression from body movement due to intrinsic protection mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration

et al. 2020

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Neurons are subjected to strain due to body movement and their location within organs and tissues. However, how they withstand these forces over the lifetime of an organism is still poorly understood. Here, focusing on touch receptor neuron-epidermis interactions using Caenorhabditis elegans as a model system, we show that UNC-70/β-spectrin and TBC-10, a conserved GTPase-activating protein, function non-cell-autonomously within the epidermis to dynamically maintain attachment of the axon. We reveal that, in response to strain, UNC-70/β-spectrin and TBC-10 stabilize trans-epidermal hemidesmosome attachment structures which otherwise become lost, causing axonal breakage and degeneration. Furthermore, we show that TBC-10 regulates axonal attachment and maintenance by inactivating RAB-35, and reveal functional conservation of these molecules with their vertebrate orthologs. Finally, we demonstrate that β-spectrin functions in this context non-cell-autonomously. We propose a model in which mechanically resistant epidermal attachment structures are maintained by UNC-70/β-spectrin and TBC-10 during movement, preventing axonal detachment and degeneration.

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Section: Discussionmentioning

confidence: 99%

Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration

et al. 2020

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“…4 and 5). Heterochronic genes are known to function in neurons (8)(9)(10)(11)(12). We propose that heterochronic genes impact synapses in the DA9 neuron and alter axodendritic polarity.…”

Section: Discussionmentioning

confidence: 96%

“…For example, the heterochronic gene lin-14 regulates the timing of synaptic remodeling during larval stage 1 (L1) in the GABAergic Dorsal D (DD) motorneurons (8). LIN-14 also regulates the timing of axon guidance in the AVM, PVM, and PVT neurons (9,10), and axon degeneration in the PLM neurons (11). Another C. elegans heterochronic gene, the conserved let-7 miRNA gene, mediates the age-dependent decline in axon regeneration (12).…”

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confidence: 99%

Regulation of Caenorhabditis elegans neuronal polarity by heterochronic genes

Armakola

Ruvkun

2019

Proc. Natl. Acad. Sci. U.S.A.

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Many neurons display characteristic patterns of synaptic connections that are under genetic control. The Caenorhabditis elegans DA cholinergic motor neurons form synaptic connections only on their dorsal axons. We explored the genetic pathways that specify this polarity by screening for gene inactivations and mutations that disrupt this normal polarity of a DA motorneuron. A RAB-3::GFP fusion protein that is normally localized to presynaptic terminals along the dorsal axon of the DA9 motorneuron was used to screen for gene inactivations that disrupt the DA9 motorneuron polarity. This screen identified heterochronic genes as major regulators of DA neuron presynaptic polarity. In many heterochronic mutants, presynapses of this cholinergic motoneuron are mislocalized to the dendrite at the ventral side: inactivation of the blmp-1 transcription factor gene, the lin-29/Zn finger transcription factor, lin-28/RNA binding protein, and the let-7miRNA gene all disrupt the presynaptic polarity of this DA cholinergic neuron. We also show that the dre-1/F box heterochronic gene functions early in development to control maintenance of polarity at later stages, and that a mutation in the let-7 heterochronic miRNA gene causes dendritic misplacement of RAB-3 presynaptic markers that colocalize with muscle postsynaptic terminals ectopically. We propose that heterochronic genes are components in the UNC-6/Netrin pathway of synaptic polarity of these neurons. These findings highlight the role of heterochronic genes in postmitotic neuronal patterning events.

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“…lin-4 and lin-14 were first discovered and characterized for their role in controlling the temporal progression of mitotic cell types such as epithelial or reproductive cells in C. elegans (Rougvie and Moss, 2013). In the post-mitotic nervous system of C. elegans, some case studies in a few neuron types have characterized the role of lin-4/lin-14 in controlling the temporal transitions in key neurodevelopmental events such as synaptic rewiring, axonal extension/branching, synaptogenesis and axonal degeneration (Hallam and Jin, 1998;Howell et al, 2015;Olsson-Carter and Slack, 2010;Ritchie et al, 2017;Xu and Quinn, 2016;Zou et al, 2012). Here, by profiling the adult neuronal transcriptome of lin-4 and lin-14 mutants, we demonstrated that they broadly regulated the temporal transitions in the expression of many but not all developmentally-regulated genes in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

Temporal transitions in post-mitotic neurons throughout theC. elegansnervous system

Sun

Hobert

2020

Preprint

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SUMMARYIn most animals, the majority of the nervous system is generated and assembled into neuronal circuits during embryonic development. However, during juvenile stages, nervous systems still undergo extensive anatomical and functional changes to eventually form a fully mature nervous system by the adult stage. The molecular changes in post-mitotic neurons across post-embryonic development and the genetic programs that control these temporal transitions are not well understood. Using the model organism C. elegans, we comprehensively characterized the distinct functional states (locomotor behavior) and corresponding distinct molecular states (transcriptome) of the post-mitotic nervous system across temporal transitions from early post-embryonic periods to adulthood. We observed pervasive changes in gene expression, many of which are controlled by the developmental upregulation of the conserved heterochronic miRNA lin-4/mir-125 and the subsequent promotion of a mature neuronal transcriptional program through the repression of its target, the transcription factor lin-14. The functional relevance of these molecular transitions are exemplified by a temporally regulated target gene of the lin-14 transcription factor, nlp-45, a neuropeptide-encoding gene. We found that nlp-45 is required for temporal transitions in exploratory activity across larval stages, across sexual maturation, and into a diapause arrest stage. Our studies provide new insights into regulatory strategies that control neuron-type specific gene batteries to modulate distinct behaviors states across temporal, sex and environmental dimensions of post-embryonic development, and also provides a rich atlas of post-embryonic molecular changes to uncover additional regulatory mechanisms.

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The Heterochronic Gene lin-14 Controls Axonal Degeneration in C. elegans Neurons

Cited by 9 publications

References 67 publications

Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration

Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration

Regulation of Caenorhabditis elegans neuronal polarity by heterochronic genes

Temporal transitions in post-mitotic neurons throughout theC. elegansnervous system

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