FLP-15 modulates the amplitude of body bends during locomotion in Caenorhabditis elegans

FLP-15 modulates the amplitude of body bends during locomotion in Caenorhabditis elegans | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results FLP-15 modulates the amplitude of body bends during locomotion in Caenorhabditis elegans Umer Saleem Bhat , H Sharanya , Siju Surendran , Namra Tasnim , View ORCID Profile Kavita Babu doi: https://doi.org/10.1101/2025.05.08.652979 Umer Saleem Bhat 1 Centre for Neuroscience, Indian Institute of Science (IISc) , Bangalore, Karnataka, India 2 Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali , Sector 81, SAS Nagar, Manauli, Punjab, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: kavitababu{at}iisc.ac.in umerusb3{at}gmail.com H Sharanya 1 Centre for Neuroscience, Indian Institute of Science (IISc) , Bangalore, Karnataka, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Siju Surendran 1 Centre for Neuroscience, Indian Institute of Science (IISc) , Bangalore, Karnataka, India 3 Université de Fribourg , Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Namra Tasnim 1 Centre for Neuroscience, Indian Institute of Science (IISc) , Bangalore, Karnataka, India 4 BRIC-National Institute of Immunology , New Delhi, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kavita Babu 1 Centre for Neuroscience, Indian Institute of Science (IISc) , Bangalore, Karnataka, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kavita Babu For correspondence: kavitababu{at}iisc.ac.in umerusb3{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract Locomotion is essential for executing most behaviours. In Caenorhabditis elegans . Efficient locomotion is exhibited as a result of the coordination of excitatory and inhibitory signals from the nervous system onto the body-wall muscles. Although neurotransmitters play a vital role in maintaining and executing coordinated movements, neuropeptides have emerged as important players in the regulation and sustenance of locomotory states. In our previous study we explored the role of the neuropeptide FLP-15 in regulating reversal frequency during foraging behaviour in C. elegans . We were also interested in exploring other possible locomotory defects in flp-15 mutant animals. In this work we show that flp-15 mutants show an increased length of reversals during foraging resulting in defects in maintaining the direction of reversals. Mutants in flp-15 exhibited a “floral” pattern of reversals as opposed to near linear patterns of reversal in wild-type control animals. We further show that the defect in maintaining the direction of reversals could be due to increased amplitude of the body-bends with flp-15 mutants showing a large increase in the mean amplitude of body-bends. Our data suggests that FLP-15 partially functions through the G-protein coupled receptor (GPCR), NPR-3, to regulates the amplitude of body-bends. Finally, we show that loss of flp-15 leads to an increase in the expression of another neuropeptide, NLP-12, whose over expression has been implicated in causing increased amplitude of body-bends allowing us to speculate that the regulation of NLP-12 by FLP-15 may allow for the observed locomotory defects in flp-15 mutant animals. Introduction Locomotion is a fundamental aspect of behaviour in many organisms, enabling essential activities such as foraging for food, avoiding predators or aversive stimuli, and mating (reviewed in ( Domenici et al , 2007 )). In Caenorhabditis elegans , locomotion is crucial for the animal’s survival and reproductive success. This locomotion is characterised by a sinusoidal wave-like motion along the dorsoventral axis. This wave-like motion is generated through a finely tuned coordination of neural and muscular activities ( Alfonso et al , 1993 ; McIntire et al , 1993a ; McIntire et al , 1993b ; White et al , 1976 , 1986). The nervous system and musculature of C. elegans are arranged in a way that allows for efficient and smooth movement, highlighting the intricate relationship between neural signalling and muscular response ( White et al ., 1986 ). The ventral nerve cord in C. elegans plays a central role in this locomotion by harbouring the cell bodies of key motor neurons. Among these are the excitatory cholinergic motor neurons, specifically the A and B-type neurons, which are responsible for stimulating muscle contraction ( Alfonso et al ., 1993 ; Jospin et al , 2009 ). These neurons release the neurotransmitter acetylcholine, which binds to receptors on the muscle cells, causing them to contract and generate movement. This excitation is essential for initiating and maintaining the forward and backward waves of movement that characterizes locomotion in C elegans ( Jospin et al ., 2009 ). In contrast, the inhibitory GABAergic motor neurons, known as D-type neurons, modulate activity by preventing excessive muscle contractions, thereby ensuring balanced and coordinated movements ( Kreyden et al , 2020 ; Liu et al , 2020 ; McIntire et al ., 1993a ; McIntire et al ., 1993b ; Safdie et al , 2016 ). These neurons release gamma-aminobutyric acid (GABA), which inhibits muscle activity on the side opposite to the contraction, allowing for the undulating wave pattern necessary for smooth locomotion. The interplay between excitatory and inhibitory signals ensures that C. elegans can move efficiently and respond dynamically to its environment. Therefore, maintaining a critical balance between excitation and inhibition is essential for the execution of normal sinusoidal movement. This balance ensures that motor functions are properly regulated, allowing for smooth and coordinated locomotion (reviewed in ( Thapliyal & Babu, 2018 )). Previous studies have highlighted the role of neuropeptides in regulating acetylcholine release at the neuromuscular junction (NMJ) in C. elegans ( Bhattacharya et al, 2014 ; Hu et al, 2011 ; Sieburth et al, 2005 ). Studies have found that mutants lacking enzymes crucial for neuropeptide maturation showed reduced acetylcholine release. Specifically, C. elegans deficient in carboxypeptidase E (encoded by egl-21 ) and proprotein convertase (encoded by egl-3 ) exhibited lower levels of acetylcholine release at the NMJ compared to wild-type animals ( Jacob & Kaplan, 2003 ; Kass et al , 2001 ). These enzymes are essential for processing prepropeptides into mature neuropeptides, suggesting that proper neuropeptide maturation is critical for maintaining normal acetylcholine levels and subsequently normal motor function. Although multiple studies have explored the role of neuropeptidergic modulation in maintaining the excitation/inhibition (E/I) balance and neurotransmitter release ( Banerjee et al , 2017 ; Bhattacharya et al ., 2014 ; Flavell et al , 2013 ; Florman & Alkema, 2022 ; Hu et al ., 2011 ; Jacob & Kaplan, 2003 ; Ji et al , 2023 ; Lim et al , 2016 ; Oranth et al , 2018 ; Pandey et al , 2021 ; Shahi et al , 2025 ; Stawicki et al , 2013 ), the function of a number of neuropeptides involved in this process remains unknown. As an example, neuropeptides like NLP-12 and FLP-18 have so far been shown to play critical roles in feedback mechanisms and homeostatic processes that ensure proper motor control ( Bhardwaj et al , 2018 ; Bhattacharya et al ., 2014 ; Hu et al ., 2011 ; Hu et al , 2015 ; Hums et al , 2016 ; Pandey et al ., 2021 ; Ramachandran et al , 2021 ; Stawicki et al ., 2013 ; Tao et al , 2019 ). The neuropeptidergic modulation of neurotransmitter release at the NMJ represents a sophisticated level of regulation that is vital for coordinated movement and behavioural responses (reviewed in ( Bhat et al , 2021 ; Li & Kim, 2008 )). Understanding the molecular basis of how neuropeptides can significantly influence the release of neurotransmitters and, consequently affect locomotory behaviour will allow for a more complete understanding of the role of neuropeptides in multiple behaviours. These findings have potential implications for understanding similar processes in other organisms and could provide insights into motor control disorders and neurodegenerative diseases where E/I balance is disrupted across phyla ( Barbour et al , 2024 ; Bi et al , 2020 ; Ghatak et al , 2021 ; Maestu et al , 2021 ). Here, we show that the neuropeptide FLP-15 regulates the amplitude of body-bends in C. elegans , where flp-15 mutants show a stark increase in the amplitude of body-bends. Our data suggests two possible pathways for modulation of the amplitude of body-bends in flp-15 mutants, one via the GPCR receptor NPR-3 expressed in dopaminergic neurons and the other through the modulation of another neuropeptide, NLP-12. Materials and Methods Strains maintenance All strains were cultured on nematode growth medium (NGM) plates, inoculated with OP50 E. coli bacteria, and maintained under standard conditions at 22°C, following established protocols outlined in previous literature ( Brenner, 1974 ). The N2 Bristol strain served as the standard wild-type (WT) control for comparative analyses across all experimental procedures. A synchronous population of young adult C. elegans was obtained using previously established protocol ( Porta-de-la-Riva et al , 2012 ). The list of strains used in this study is tabulated in Supplementary Table 1 (S1). Molecular biology and transgenes Transcriptional reporters were generated through molecular cloning of the promoter regions, positioning them upstream to fluorescent protein (GFP) in the pPD95.75 vector or mCherry in the pPD49.26 vector. The length of all promoter sequences was maintained at 2 kb, spanning the genomic region upstream of the start codon for each respective gene and the sequences were extracted from WormBase. Promoters of genes flp-15, gur-3, npr-3, dat-1 and nlp-12 have been used in this study. The rescue constructs were generated by cloning genomic DNA or cDNA downstream of the respective promoter. All the constructs were microinjected in C. elegans to prepare transgenic lines as previously described ( Mello & Fire, 1995 ; Mello et al , 1991 ). The list of primers and plasmids used in this study is tabulated in Supplementary Tables 2 and 3 (S2 and S3) respectively. Behavioural assays All the behavioural assays were performed using single young adult staged C. elegans recorded one at a time across several days to ensure consistency and account for variability. Briefly, a well-fed young adult animal was picked with an eye lash pick by using a small drop of halocarbon oil, ensuring a gentle transfer. The C. elegans was then placed in an off food NGM plate and allowed to crawl freely for one minute to get rid of any residual food. The C. elegans was then gently picked again and placed on the freshly prepared 90 mm NGM (without cholesterol) plate calibrated at room temperature and allowed to move freely for one minute before starting the tracking of the animal. The movement of the animal was recorded for 5 minutes at 8 fps using the MBF Bioscience WormLab imaging system ( Roussel et al , 2014 ). The reversal length was calculated for each reversal and averaged over the total number of reversals made over five minutes which was then plotted as single data point. Trajectory of C. elegans and amplitude of the body-bends were analysed with the help of WormLab software (MBF Bioscience). The number of C. elegans recorded for each genotype was ≥ 20. Quantitative PCR Total RNA was isolated from well fed synchronized adult animals (48h including hatching time). 100ng of total RNA was used to synthesize cDNA using Transcriptor High Fidelity cDNA Synthesis Kit (Roche). Real time PCR was performed using LightCycler 480 SYBR Green I Master (Roche) and LightCycler Instrument (BioRad). The analysis of gene expression was done as previously described using the formula The expression of gene of interest ( nlp-12 ) was analysed in WT, flp-15 and npr-3 mutant C. elegans . The fold increase in gene expression was determined as previously described using formula for fold change = 2 - ΔΔCt ( Livak & Schmittgen, 2001 ). Statistical analysis The data was plotted on GraphPad Prism 10 and represented as violin plots and bar graphs according to the distribution of data. Error bars represent SEM. One-way ANOVA with multiple comparison and post-hoc tukey tests was performed to compare the results in all the experiments. The level of significance was set as p≤ 0.05. Results FLP-15 is required to maintain the direction of reversals Reorientations including reversals and omega-turns, are critical for food searching behaviours in Caenorhabditis elegans . Bhardwaj et al. has shown that the length of reversals is important in determining the extent of the turning angle during reorientation events. Shorter reversals are usually associated with turning angles < 90 degree, while longer reversals are attribute to turning angle between 90-180 degree and in most instances culminate in omega-turns. The study further show that FLP-18 plays a critical role in regulating reversal length in C. elegans ( Bhardwaj et al ., 2018 ). We were interested in further understanding the role of neuropeptides in the regulation of reversal length (Illustrated in Figure 1A ). To this end we performed a screen using 22 mutants in neuropeptides to study the role of other neuropeptidergic mutants in regulating reversal length ( Bhat et al , 2025 ). We observed a significant increase in the length of reversals in flp-15 mutants when compared to wild-type (WT) control animals ( Figure 1B ). Further, this phenotype seen in the mutants was rescued by expressing FLP-15 under its own promoter ( Figure 1B ). This finding suggests that FLP-15 plays a crucial role in maintaining normal reversal length. While observing the length of reversals, we noted an intriguing phenotype in flp-15 mutant C. elegans . Unlike WT animals that execute reversals in a stereotypic near-straight backward direction, flp-15 mutants formed a “floral” pattern during reversals (depicted in Figure 1C ). This abnormal pattern suggests a significant deviation from the normal movement typically seen in C. elegans . The floral pattern observed in flp-15 indicates a disruption in the coordinated control of body-bends during reversals. This disruption is likely due to an imbalance in the excitatory and inhibitory signals that regulate muscle contractions during movement (reviewed in ( Wen et al , 2018 )). Download figure Open in new tab Figure 1: Mutants in flp-15 show increased body-bends per reversal (A) Schematic showing body bends (head turning) during reversals, with each number indicating a complete body bend as the head moves in the opposite direction. (B) Quantification of the body bend per reversals. Mutants in flp-15 show a significant increase in the number of body bends during reversals (reversal length) compared to the wild-type (WT) counterparts. In this plot, each dot corresponds to the number of body bends per reversal from a single C. elegans . Statistical significance was determined using One-way ANOVA with the Tukey test and represented by “ns” for not significant and “****” for p< 0.0001. (C) Tracks of C. elegans during locomotion. The insets in each track indicate the region containing the dotted square. The insets indicate the linear reversals in WT animals and the floral pattern of reversals in flp-15 mutants. To our knowledge there appears to be no previous literature discussing these abnormal reversal patterns in C. elegans . Our findings suggest that in addition to length of reversals, maintaining a proper direction of reversal is critical for efficient locomotion and foraging. Proper reversal direction is essential for the effective execution of reorientation movements, which are vital for C. elegans to navigate their environment, locate food, and avoid predators. We next examined the locomotion of flp-15 mutants in some detail and found that flp-15 is required to maintain the amplitude of body-bends in C. elegans . FLP-15 regulates the amplitude of body-bends in Caenorhabditis elegans While carefully observing this intriguing defect in the directionality of reversals, we suspected that the ‘floral’ pattern observed in flp-15 mutants was due to increased amplitude of body-bends. This increased amplitude likely causes exaggerated curvatures while executing reversals, leading to the abnormal reversal patterns seen. To test this hypothesis, we quantified the amplitude of body-bends during forward and reverse movements separately (Illustrated in Figure 2A ). We observed that WT animals exhibit higher body-bend amplitude during reversals when compared to making forward movements ( Figure 2B ). Interestingly in flp-15 mutant animals there was an increase of amplitude during both forward as well as reverse movements when compared to control C. elegans , suggesting a global amplitude defect in these mutants ( Figure 2B ). To further explore this defect, we quantified the mean amplitude of body-bends across the entire trajectory of the animals (including forward and reverse movements). Our results confirmed that flp-15 mutants exhibited a significantly large increase in the mean amplitude of body-bends when compared to WT C. elegans ( Figure 2C ). This increased curvature during reversals supports our idea that altered body-bend amplitudes may contribute to the defective directionality in flp-15 mutants. To further validate our findings, we attempted to rescue this defect by supplementing flp-15 mutants with FLP-15 cDNA under the control of its endogenous promoter and specifically in the I2 neurons ( gur-3 promoter) where FLP-15 is expressed ( Bhat et al ., 2025 ). These interventions partially restored the body-bend amplitude in the flp-15 mutant animals ( Figure 2C ). These results suggest that the neuropeptide FLP-15 regulates the body-bend amplitude during locomotion to maintain normal locomotion including proper reversal direction. We were next interested in understanding the receptor through which FLP-15 could be functioning to maintain normal body-bends in the animal. Download figure Open in new tab Figure 2: Mutants in flp-15 show increased amplitude of body-bends per reversal (A) Schematic showing the measurement of amplitude of body bend during locomotion. The green line indicates the amplitude, and the blue line indicates the baseline of the sinusoidal wave during the movement. The mean of the amplitude is calculated for 5 minutes per C. elegans and averaged over multiple animals. (B) Quantification of the mean amplitude during forward and reversal locomotion. Mutant in flp-15 show a significant increase in the mean amplitude during both forward and reversal locomotion compared to their WT counterparts. In this plot, each dot corresponds to the mean amplitude from a single animal. (C) Quantification of the mean amplitude during the entire trajectory of the animal. Mutants in flp-15 displayed global defects in the amplitude of body-bends throughout the entire trajectory. The defect was largely rescued by supplementing flp-15 extrachromosomally under the control of its endogenous promoter and partially by expressing flp-15 under the I2 neuron-specific promoter (P gur-3 ). Statistical significance was determined for B and C using One-way ANOVA with the Tukey test and represented by “**”, “***’’ or “****” for p-values less than 0.01, 0.001, or 0.0001, respectively. FLP-15 regulates the amplitude of body-bends partially through the NPR-3 receptor Previous work has implicated NPR-3 as a putative receptor for FLP-15 ( Beets et al , 2023 ). Moreover, our recent study suggests that FLP-15 functions through NPR-3 to regulate the frequency of reversals during foraging ( Bhat et al ., 2025 ). We tested whether FLP-15 functions through NPR-3 in regulating the amplitude of body-bends. Our results indicated that npr-3 mutants show a significant increase in the amplitude of body-bends as compared to WT animals, but this defect is not as severe as that seen in flp-15 mutants ( Figure 3A ). These data suggest that NPR-3 may be a receptor involved and likely not the only receptor that binds to FLP-15 to regulate the amplitude of body-bends. We next went on to test the body-bend amplitude in flp-15; npr-3 double mutant animals and found that the double mutants showed a phenotype similar to that seen in flp-15 single mutants (non-additive), indicating that flp-15 and npr-3 may be functioning in the same pathway to regulate the amplitude of body-bends ( Figure 3A ). We next overexpressed FLP-15 under its own promoter in flp-15 and npr-3 mutant C. elegans . Download figure Open in new tab Figure 3: FLP-15 functions partially through NPR-3 to maintain the amplitude of body-bends (A) Quantification of mean amplitude. The mutants in flp-15, npr-3 and flp-15; npr-3 double mutants show defects in the amplitude of body-bends during locomotion. This indicates that flp-15 may function partially through npr-3 . (B) Overexpression of the flp-15 gene in the npr-3 mutant background does not alleviate the defects in the amplitude of body-bends, indicating again that flp-15 may function partially through npr-3 to regulate the amplitude of the body-bends. Statistical significance in A and B was determined using One-way ANOVA with the Tukey test and represented by “ns” for not significant, “**”, “***’’ or “****” for p-values less than 0.01, 0.001, or 0.0001, respectively+ We found that flp-15 mutants show a partial rescue while npr-3 mutants do not show any change in the increased amplitude of body-bends phenotype ( Figure 3B ). These data suggest that overexpressing FLP-15 in the absence of npr-3 does not circumvent the npr-3 mutant phenotype, again indicating that FLP-15 functions through NPR-3. We were next interested in studying the site of action of NPR-3 for its role in regulating the amplitude of body-bends in C. elegans . FLP-15 regulates the amplitude of body-bends partially through NPR-3 expressed in dopaminergic neurons To further explore the downstream neurons where NPR-3 may be functioning, we conducted neuron-specific rescue experiments in npr-3 mutant C. elegans . Our previous study has suggested that NPR-3 is expressed in ADE and CEP dopaminergic neurons in the head and the DVA neuron in the tail ( Bhat et al ., 2025 ). We first supplemented the npr-3 mutants with an extrachromosomal array of wild type NPR-3 genomic DNA (gDNA) under the control of its endogenous promoter. We were able to completely rescue the increased amplitude of body-bends in these animals ( Figure 4A ). We next expressed the NPR-3 gDNA specifically in dopaminergic neurons using the dat-1 promoter ( Nass et al , 2002 ; Nass et al , 2001 ) or DVA neurons using the nlp-12 promoter ( Bhattacharya et al ., 2014 ; Hu et al ., 2011 ), in npr-3 mutants. Our results showed that we were able to partially rescues the defect in the amplitude of body-bend when NPR-3 was supplemented in dopaminergic neurons, however we did not find a significant rescue when NPR-3 was expressed in DVA neurons ( Figure 4A ). We next asked if dopamine could be involved in this behavioural output. To this end we analysed cat-2 mutant C. elegans that lack the dopamine synthesis enzyme ( Sanyal et al , 2004 ). We saw that cat-2 mutants showed a small increase in amplitude of body-bends similar to but to a lower degree than that seen in npr-3 mutants ( Figure 4B ). These data suggest that dopamine signalling through NPR-3 may be involved in regulating the amplitude of body-bends. Download figure Open in new tab Figure 4: NPR-3 functions in dopaminergic neurons to allow for normal amplitude of body-bends (A) Quantification of mean amplitude of body bend. The data shows that supplementing npr-3 gene under the control of its endogenous promoter in the npr-3 mutant background completely rescues the increased body-bend amplitude phenotype. Additionally, the phenotype is partially rescued when npr-3 gene is supplemented under the control of the dat-1 promoter, that drives expression of NPR-3 in dopaminergic neurons. Although the increased amplitude of body-bends phenotype is not rescued by expressing npr-3 specifically in DVA neurons, however, there seems to be a decrease in the mean amplitude of body-bends in the rescuing line. These data indicate that dopaminergic neurons are involved in regulating npr-3 dependent increase in amplitude of body-bends. (B) The data shows that mutants in cat-2 display an increased amplitude of body-bends, however the defect is not as severe as that seen in npr-3 mutants . Statistical significance in A and B was determined using One-way ANOVA with the Tukey test and represented by “ns” for not significant, “**”, “***’’ or “****” for p-values less than 0.01, 0.001, or 0.0001, respectively Together, these findings highlight the role of the neuropeptide FLP-15 functioning through the NPR-3 receptor to regulate normal body-bends. We next wanted to test other possible pathways through which FLP-15 may function. FLP-15 regulates the expression of NLP-12 to maintain the amplitude of body-bends Although previous studies have extensively explored the mechanisms behind the sinusoidal wave patterns in C. elegans ( Chalfie et al , 1985 ; Shingai et al , 2013 ; Wen et al , 2012 ; White et al ., 1976 ), the role of neuropeptides in this phenomenon has largely been unaddressed. A recent study by Ramachandran et al. highlighted that overexpressing the neuropeptide NLP-12, specifically expressed in the DVA neuron, results in deeper body-bends in C. elegans , suggesting a significant role for neuropeptides in modulating this behaviour ( Ramachandran et al ., 2021 ). Given that flp-15 mutant animals exhibited a similar increase in the amplitude of body-bends, we decided to investigate the expression of NLP-12 in both flp-15 and npr-3 mutants using qPCR. The rationale was to see if changes in NLP-12 expression levels could explain the observed phenotype. Our data revealed that NLP-12 was significantly higher in flp-15 mutants when compared to WT animals. In contrast, npr-3 mutants showed only a slight increase in NLP-12 gene expression ( Figure 5A ). Based on these results, we hypothesized that loss of flp-15 and subsequent increase in NLP-12 expression leads to an increase in the amplitude of body-bends. To test this hypothesis, we conducted behavioural experiments of nlp-12, and nlp-12; flp-15 mutant C. elegans . For the hypothesis to be true we anticipated that mutating the nlp-12 gene in flp-15 mutant C. elegans would mitigate the increased amplitude defect, restoring the amplitude of body-bends closer to WT levels. Our results showed that nlp-12 mutants C. elegans show a small but significant decrease in the amplitude of body-bends when compared to the wild type animals ( Figure 5B ). Further, we saw that in nlp-12; flp-15 double mutants, the amplitude of body-bends was significantly reduced in comparison to flp-15 mutants and was non-significant from the amplitude of body-bends of WT animals and nlp-12 mutant C. elegans ( Figure 5B ). These results suggest that the increased amplitude of body-bends observed in flp-15 mutants are due to the overexpression of NLP-12. The slight overexpression in npr-3 mutants indicates that while NPR-3 might contribute to this phenotype, we cannot exclude the possibility that other FLP-15 receptors might also be involved in this process. Download figure Open in new tab Figure 5: Mutants in flp-15 show increased nlp-12 levels (A) qPCR data shows that flp-15 mutants show an approximately three-fold increase in the expression of nlp-12 . However, there is only a 1.5-fold increase of nlp-12 in npr-3 mutants. Each bar apart from WT represents the average fold change in nlp-12 expression in the corresponding mutant background. The error bars represented SEM. (B) Quantification of mean amplitude in nlp-12 mutants showed that there was a significant decrease in the amplitude of body bend during locomotion. Additionally, introducing flp-15 mutation in the nlp-12 mutant background leads to a decrease in the mean amplitude of body bend. Statistical significance in A and B was determined using One-way ANOVA with the Tukey test and represented by “ns” for not significant, “*” or “****” for p-values less than 0.05, or 0.0001 respectively. Taken together, our work identifies FLP-15 as a novel regulator of the amplitude of body-bends in C. elegans . Further, we show that FLP-15 may function through NPR-3 in dopaminergic neurons to regulate the amplitude of body-bends. Finally, our data also suggests that FLP-15 may function via DVA, possibly through other receptor/s to modulate NLP-12 levels that also appears to affect body-bends in C. elegans (Illustrated in Figure 6 ). Download figure Open in new tab Figure 6: Model indicating how FLP-15 may regulate the amplitude of body-bends Our data indicates that FLP-15 may function through dopaminergic neurons as well as regulate NLP-12 levels to allow for maintaining the amplitude of body bends in WT C. elegans . Discussion Caenorhabditis elegans locomotion is characterized by distinct patterns, including forward movement, reversals, and omega turns ( Gray et al , 2005 ). Despite numerous studies investigating the neural circuitry controlling these locomotory behaviours, the underlying mechanisms and molecular players remain largely unknown. Most research has focused on the mechanisms governing the frequency of reversals, leaving a gap in understanding aspects of body-bends and the mechanisms underlying them ( Bhardwaj et al , 2020 ; Cohen et al , 2009 ; Gray et al ., 2005 ; Piggott et al , 2011 ). Neuropeptides have emerged as crucial regulatory molecules modulating specific locomotor characteristics. They play a significant role in fine-tuning the locomotory circuit in C. elegans , influencing not only the frequency of reversals but also other aspects of movement. A study by Hu et al. explored the neuropeptide NLP-12 and its role in a feedback loop that regulates cholinergic transmission at the NMJ. They found that NLP-12 is secreted from stretch-sensitive DVA neurons during muscle contraction, which is stimulated by increased acetylcholine transmission ( Hu et al ., 2011 ). NLP-12, in turn, activates its receptor CKR-2, further enhancing cholinergic transmission at the NMJ ( Bhattacharya et al ., 2014 ; Hu et al ., 2011 ; Ramachandran et al ., 2021 ). This feedback loop underscores the complex interplay between neuropeptides and neurotransmitters in modulating motor functions and maintaining the E/I balance. The FLP-18 neuropeptide has also been implicated in modulating overexcitation in acr-2(gf) mutant C. elegans . These mutants carry a gain-of-function mutation in the nicotinic acetylcholine receptor ACR-2 subunit, which leads to overexcitation and a reduction in GABA-induced inhibition, disrupting the E/I balance. The study revealed that the acr-2(gf) mutation upregulates FLP-18, which helps restore balance by activating its receptors NPR-1 and NPR-5. These finding highlights the role of FLP-18 in counteracting the effects of overexcitation and maintaining homeostasis in neural circuits ( Jospin et al ., 2009 ; Stawicki et al ., 2013 ). These findings suggest that neuropeptidergic signalling is essential for the precise control of C. elegans locomotion Reorientations, including reversals and omega turns, are crucial for food-searching behaviours of C. elegans . Bhardwaj et al. found that the length of reversals influences the turning angle during reorientation, with shorter reversals resulting in smaller angles and longer reversals leading to larger angles and omega turns ( Bhardwaj et al ., 2018 ). In that study, FLP-18 was identified as a key regulator of reversal length. This study builds on the previous work by showing that flp-15 mutants also have significantly longer reversals compared to WT animals, indicating FLP-15’s role in maintaining normal reversal lengths. We also found that npr-3 mutants displayed increased reversal lengths, suggesting that FLP-15 and NPR-3 function in the same pathway. Furthermore, we observed that flp-15 mutants exhibited abnormal “floral” patterns during reversals, unlike the straight reversals of WT animals. This pattern, which was not as pronounced in npr-3 mutants, suggests a disruption in normal movement behaviour and efficient foraging. We hypothesized that increased body-bend amplitude in flp-15 mutants possibly caused this defect, which was confirmed through quantification of the amplitude of body-bends in flp-15 and npr-3 mutants. Rescue experiments partially restored normal body-bend amplitude and mitigated the floral pattern. Our qPCR analysis revealed that NLP-12 was significantly overexpressed in flp-15 mutants, suggesting that this overexpression contributes to the increased body-bend amplitude. These findings indicate that FLP-15 and NPR-3 are crucial in regulating both the amplitude and directionality of body-bends, highlighting the complex neuropeptidergic modulation of locomotion in C. elegans . Taken together, our data suggests that FLP-15, released from I2 neuron, functions through NPR-3 on dopaminergic neurons to regulate the length of reversals which may possibly function downstream through the release of dopamine. We also show that amplitude of body-bends which further controls the direction of reversal is regulated partially through NPR-3. Further, FLP-15 negatively regulates the expression of NLP-12 to maintain the amplitude of body-bend during locomotion (Illustrated in Figure 6 ). This highlights a potential mechanism where neuropeptide regulation plays a crucial role in controlling amplitude of body-bends in C. elegans , providing new insights into the complex neuropeptidergic modulation of locomotion. Funding The work was supported by a DBT Grant [no. BT/PR24038/BRB/10/1693/2018] and part funded by a DBT/Welcome Trust India Alliance Fellowship [grant number IA/S/19/2/504649], a DBT Janaki Ammal National Women Bioscientist Award [no. BT/HRD-NBA-NWB/38/2019-20], an ANRF Core Research grant [no. CRG/2023/001950], and an ANRF-POWER grant [no. SPG/2022/000182] awarded to KB. USB and SH were supported by DBT-JRF and DBT-SRF fellowships. The funders had no role in experimental design, data collection or analysis, decision to publish, or preparation of the manuscript. Author Contributions USB: Design and execution of experiments, data analyses, manuscript writing/editing, SH: Execution of experiments, data analyses and manuscript editing, SS: Outcrossing and behavioural screen, NT: Molecular biology experiments, and KB: Supervision, funding acquisition and manuscript writing/editing. Conflict of Interest Authors declare no conflict of interests. Acknowledgements Some strains were provided by CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). All illustrations were created in BioRender. We thank Faraz Abbas, Imra Aftab and Velu Saravanan for help with experiments. We also thank Palagiri Suresh for routine help and the members of Kavita Babu’s lab for suggestions and critique on the manuscript. 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Share FLP-15 modulates the amplitude of body bends during locomotion in Caenorhabditis elegans Umer Saleem Bhat , H Sharanya , Siju Surendran , Namra Tasnim , Kavita Babu bioRxiv 2025.05.08.652979; doi: https://doi.org/10.1101/2025.05.08.652979 Share This Article: Copy Citation Tools FLP-15 modulates the amplitude of body bends during locomotion in Caenorhabditis elegans Umer Saleem Bhat , H Sharanya , Siju Surendran , Namra Tasnim , Kavita Babu bioRxiv 2025.05.08.652979; doi: https://doi.org/10.1101/2025.05.08.652979 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Neuroscience Subject Areas All Articles Animal Behavior and Cognition (7624) Biochemistry (17650) Bioengineering (13871) Bioinformatics (41882) Biophysics (21424) Cancer Biology (18566) Cell Biology (25461) Clinical Trials (138) Developmental Biology (13365) Ecology (19867) Epidemiology (2067) Evolutionary Biology (24290) Genetics (15590) Genomics (22476) Immunology (17713) Microbiology (40331) Molecular Biology (17148) Neuroscience (88477) Paleontology (666) Pathology (2828) Pharmacology and Toxicology (4816) Physiology (7635) Plant Biology (15114) Scientific Communication and Education (2044) Synthetic Biology (4286) Systems Biology (9815) Zoology (2268)