Biology subjects

Murphy, C. T.

Publications and source records attributed to Murphy, C. T..

30 records · Page 2Linked to original sources

bioRxiv2020

Males deploy multifaceted strategies and hijack longevity pathways to induce premature demise of the opposite sex

Interactions between the sexes negatively impact health in many species, including mammals1–9. In mice, sexual interactions induce weight gain and shorten lifespan in females, independent of fertilization6,9. In Caenorhabditis, males shorten the lifespan of the opposite sex (females or hermaphrodites)1–3,8. However, the mechanisms underlying the negative influence of males on lifespan – and their overlap with known longevity pathways – are still largely unknown. Here, we use transcriptomic profiling and targeted screens to systematically uncover new conserved genes involved in male-induced demise. Interestingly, deficiency of these genes individually, and especially in combination, induces strong protection, highlighting the benefit of combining interventions to extend lifespan. Some genes (e.g. acbp-3, col-43) only extend hermaphrodite lifespan when knocked-down in the presence of males, suggesting specific protective mechanisms against male-induced demise. However, we also uncover two previously unknown longevity genes (sri-40 and delm-2) that, when knocked-down, extend hermaphrodite lifespan both with and without males, which points to new broad mechanisms of resistance. In sharp contrast, many classical long-lived mutants are actually short-lived in the presence of males, suggesting that males hijack and suppress known longevity pathways. This systematic analysis reveals striking differences in longevity in single sex versus mixed sex environments and uncovers the elaborate network of functional regulation elicited by sexual interactions, which could extend to other species.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2020

Flow over seal whiskers: significance of geometricfeatures on force and frequency response

The complex undulated geometry of seal whiskers has been shown to substantially modify the turbulent structures directly downstream, resulting in a reduction of hydrodynamic forces as well as modified vortex-induced-vibration response when compared with smooth whiskers. Although the unique hydrodynamic response has been well documented, an understanding of the fluid flow effects from each geometric feature remains incomplete. In this computational investigation, nondimensional geometric parameters of the seal whisker morphology are defined in terms of their hydrodynamic relevance, such that wavelength, aspect ratio, undulation amplitudes, symmetry and undulation off-set can be varied independently of one another. A two-factor fractional factorial design of experiments procedure is used to create 16 unique geometries, each of which dramatically amplifies or attenuates the geometric parameters compared with the baseline model. The flow over each unique topography is computed with a large-eddy simulation at a Reynolds number of 500 with respect to the mean whisker thickness and the effects on force and frequency are recorded. The results determine the specific fluid flow impact of each geometric feature which will inform both biologists and engineers who seek to understand the impact of whisker morphology or lay out a framework for biomimetic design of undulated structures.

biophysics↗

bioRxiv2020

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

Evolutionarily conserved signaling pathways are crucial for adjusting growth, reproduction, and cell maintenance in response to altered environmental conditions or energy balance. However, we have an incomplete understanding of the signaling networks and mechanistic changes that coordinate physiological changes across tissues. We found that loss of the cAMP response element-binding protein (CREB) transcription factor significantly slows Caenorhabditis elegans reproductive decline, an early hallmark of aging in many animals. Our results indicate that CREB acts downstream of the transforming growth factor beta (TGF-{beta}) Sma/Mab pathway in the hypodermis to control reproductive aging, and that it does so by regulating a Hedgehog-related signaling factor, WRT-10. Overexpression of hypodermal wrt-10 is sufficient to delay reproductive decline and oocyte quality deterioration, potentially acting via Patched-related receptors in the germline. This TGF-{beta}/CREB/WRT-10 signaling axis allows a key metabolic tissue to communicate with the reproductive system to regulate oocyte quality and the rate of reproductive decline. HighlightsO_LIThe transcription factor CREB regulates oocyte quality and reproductive decline C_LIO_LIHypodermal CREB downstream of TGF-{beta} Sma/Mab signaling controls reproductive aging C_LIO_LICREB targets in the hypodermis include a Hedgehog-related signaling factor, wrt-10 C_LIO_LIWRT-10 regulates reproductive aging, potentially via germline Patched receptors C_LI eTOC BlurbTempleman et al. describe how CREB, a highly conserved transcription factor, is a central regulator of age-dependent reproductive decline. CREB acts downstream of the TGF-{beta} Sma/Mab pathway in the hypodermis, a key Caenorhabditis elegans metabolic tissue, to control oocyte quality maintenance and the rate of reproductive decline. Hypodermal CREB affects the expression of wrt-10, which encodes a Hedgehog-related signaling factor. The authors show that wrt-10 regulates reproductive aging, potentially via Patched-related receptors in the germline.

developmental biology↗

bioRxiv2020

Metabolic defects cause hyperactive mitochondria and Parkinson disease-like traits

Metabolic dysfunction is a facet of many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood1. We recently discovered a potential causal link between the branched-chain amino acid transferase, BCAT-1, and the neurodegenerative movement disorder, Parkinsons disease (PD)2. Knockdown of C. elegans bcat-1 recapitulates PD-like features, including progressive motor deficits and neurodegeneration with age2. Using transcriptomic, metabolomic, and imaging approaches, we show that bcat-1 knockdown increases mitochondrial activity and induces oxidative damage in neurons through mTOR-independent mechanisms. We recently developed a high-throughput screening platform to identify drugs that may be repurposed for PD, and found that metformin, the leading type 2 diabetes medication, significantly improves motor function in bcat-1(RNAi) worms3. Late-in-life metformin treatment restores normal mitochondrial activity levels and protects against bcat-1-associated neurodegeneration. Our results suggest that PD may originate as a metabolic disorder, and highlight metformin as a promising new drug candidate for PD treatment.

neuroscience↗

bioRxiv2020

High-throughput behavioral screen in C. elegans reveals novel Parkinson disease drug candidates

We recently linked branched-chain amino acid transferase 1 (BCAT1) with the movement disorder Parkinsons disease (PD), and found that reduction of C. elegans bcat-1 causes abnormal spasm-like curling behavior with age. Here, we report the development of a high-throughput automated curling assay and its application to the discovery of new potential PD therapeutics. Four FDA-approved drugs were identified as candidates for late-in-life intervention, with metformin showing the greatest promise for repurposing to PD.

neuroscience↗

bioRxiv2020

C. elegans reads bacterial non-coding RNAs to learn pathogenic avoidance

C. elegans is exposed to many different bacteria in its environment, and must distinguish pathogenic from nutritious bacterial food sources. Here, we show that a single exposure to purified small RNAs isolated from pathogenic Pseudomonas aeruginosa (PA14) is sufficient to induce pathogen avoidance, both in the treated animals and in four subsequent generations of progeny. The RNA interference and piRNA pathways, the germline, and the ASI neuron are required for bacterial small RNA-induced avoidance behavior and transgenerational inheritance. A single non-coding RNA, P11, is both necessary and sufficient to convey learned avoidance of PA14, and its C. elegans target, maco-1, is required for avoidance. A natural microbiome Pseudomonas isolate, GRb0427, can induce avoidance via its small RNAs, and the wild C. elegans strain JU1580 responds similarly to bacterial sRNA. Our results suggest that this ncRNA-dependent mechanism evolved to survey the worms microbial environment, use this information to make appropriate behavioral decisions, and pass this information on to its progeny.

genetics↗

bioRxiv2019

PQM-1 controls hypoxic survival via regulation of lipid metabolism

Animals have evolved responses to low oxygen conditions to ensure their survival. Here we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial enzyme for sugar metabolism. PQM-1 promotes intestinal fat metabolism by activating the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity enhances fat accumulation in embryos under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.

genetics↗

bioRxiv2019

Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation

Presynaptic protein synthesis is important in the adult central nervous system; however, the set of mRNAs localized to presynaptic areas has yet to be identified in any organism. We differentially labeled somatic and synaptic compartments nervous system-wide in adult C. elegans and isolated synaptic regions for deep sequencing. Analysis of the synaptic transcriptome reveals that synaptic transcripts are predicted to have specialized functions in neurons. Differential expression analysis identified 543 genes enriched in synaptic regions relative to somatic regions, with synaptic functions conserved in higher organisms. We find that mRNAs for pumilio RNA-binding proteins are abundant in synaptic regions, which we confirmed through high-sensitivity in situ hybridization. We identified a new role for the PUM2 orthologs puf-7/8 as repressors of memory formation through regulation of the mitochondrial dynamics regulator, mff-1. Identification of presynaptic mRNAs provides insight into mechanisms that regulate synaptic function and behavior.

neuroscience↗

bioRxiv2019

ZIP-5/bZIP transcription factor regulation of folate metabolism is critical for aging axon regeneration

Aging is associated with reduced capacity for tissue repair, perhaps the most critical of which is a decline in the ability of aged neurons to recover after injury. Identifying factors that improve the regenerative ability of aging neurons is a prerequisite for therapy design and remains an enormous challenge, yet many of the genes that play a role in regeneration of youthful axons do not regulate axon regeneration in older animals2,9, highlighting the need to identify aging-specific regeneration mechanisms. Previously, we found that increased DAF-16/FOXO activity enhances the regenerative ability of mechanosensory axons in aged animals9. Here we show that DAF-16/FOXO mediates its pro-regenerative effects by upregulating folate metabolism genes via the ZIP-5 bZIP transcription factor. Remarkably, dietary folic acid supplementation improves the regeneration of aging C. elegans axons. Enzymes regulating folate metabolism are also up-regulated in regenerating zebrafish fins, and we show that dietary folic acid supplementation post-amputation enhances fin regrowth in aging zebrafish. Our results demonstrate that boosting folate metabolism is a conserved and non-invasive approach to increase the regenerative capacity of aging neurons and tissues. Given that lower folate status has been linked with reduced cognition in the elderly17, maintaining optimal folate metabolism may be a general strategy to achieve healthy brain aging.

neuroscience↗

bioRxiv2019

Cross-kingdom recognition of bacterial small RNAs induces transgenerational pathogenic avoidance

We recently discovered that C. elegans can pass on a learned avoidance of pathogenic Pseudomonas aeruginosa (PA14) to four generations of its progeny. This transgenerational inheritance is bacterial species-specific, but how C. elegans recognizes and distinguishes different bacteria and transmits this information to future generations is not apparent. Here we show that small RNAs purified from pathogenic PA14 are sufficient not only to induce avoidance of pathogens in mothers, but also to confer transgenerational inheritance of this species-specific behavior for four generations, all without direct contact with pathogenic bacteria. This behavior requires the small RNA transporters SID-1 and SID-2, RNA interference pathway components, the piRNA Piwi/Argonaute pathway, a functioning germline, and TGF-{beta} ligand daf-7 expression in the ASI sensory neuron. Our results suggest that C. elegans \"reads\" small RNAs expressed by pathogenic bacteria, and uses this information to induce an escape behavior that lasts for four additional generations. C. elegans may have evolved this trans-kingdom signaling system to avoid pathogens in abundant classes of bacteria in its environment and its microbiome.

genetics↗

bioRxiv2018

C. elegans pathogenic learning confers multigenerational pathogen avoidance

The ability to pass on learned information to progeny could present an evolutionary advantage for many generations. While apparently evolutionarily conserved1-12, transgenerational epigenetic inheritance (TEI) is not well understood at the molecular or behavioral levels. Here we describe our discovery that C. elegans can pass on a learned pathogenic avoidance behavior to their progeny for several generations through epigenetic mechanisms. Although worms are initially attracted to the gram-negative bacteria P. aeruginosa (PA14)13, they can learn to avoid this pathogen13. We found that prolonged PA14 exposure results in transmission of avoidance behavior to progeny that have themselves never been exposed to PA14, and this behavior persists through the fourth generation. This form of transgenerational inheritance of bacterial avoidance is specific to pathogenic P. aeruginosa, requires physical contact and infection, and is distinct from CREB-dependent long-term associative memory and larval imprinting. The TGF-{beta} ligand daf-7, whose expression increases in the ASJ upon initial exposure to PA1414, is highly expressed in the ASI neurons of progeny of trained mothers until the fourth generation, correlating with transgenerational avoidance behavior. Mutants of histone modifiers and small RNA mediators display defects in naive PA14 attraction and aversive learning. By contrast, the germline-expressed PRG-1/Piwi homolog15 is specifically required for transgenerational inheritance of avoidance behavior. Our results demonstrate a novel and natural paradigm of TEI that may optimize progeny decisions and subsequent survival in the face of changing environmental conditions.

genetics↗

bioRxiv2017

Transcriptome Analysis of Adult C. elegans Cells Reveals Tissue-specific Gene and Isoform Expression

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans four major tissues (or \"tissue-ome\"), identifying ubiquitously expressed and tissue-specific \"super-enriched\" genes. These data newly reveal the hypodermis metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms and a neuron-specific CREB isoform. Finally, we developed a machine learning-based prediction tool for 70 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-b activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals

genomics↗