Publications by authors named "Lakshmi Sundararajan"

15 Publications

  • Page 1 of 1

Actin assembly and non-muscle myosin activity drive dendrite retraction in an UNC-6/Netrin dependent self-avoidance response.

PLoS Genet 2019 06 20;15(6):e1008228. Epub 2019 Jun 20.

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America.

Dendrite growth is constrained by a self-avoidance response that induces retraction but the downstream pathways that balance these opposing mechanisms are unknown. We have proposed that the diffusible cue UNC-6(Netrin) is captured by UNC-40(DCC) for a short-range interaction with UNC-5 to trigger self-avoidance in the C. elegans PVD neuron. Here we report that the actin-polymerizing proteins UNC-34(Ena/VASP), WSP-1(WASP), UNC-73(Trio), MIG-10(Lamellipodin) and the Arp2/3 complex effect dendrite retraction in the self-avoidance response mediated by UNC-6(Netrin). The paradoxical idea that actin polymerization results in shorter rather than longer dendrites is explained by our finding that NMY-1 (non-muscle myosin II) is necessary for retraction and could therefore mediate this effect in a contractile mechanism. Our results also show that dendrite length is determined by the antagonistic effects on the actin cytoskeleton of separate sets of effectors for retraction mediated by UNC-6(Netrin) versus outgrowth promoted by the DMA-1 receptor. Thus, our findings suggest that the dendrite length depends on an intrinsic mechanism that balances distinct modes of actin assembly for growth versus retraction.
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http://dx.doi.org/10.1371/journal.pgen.1008228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605669PMC
June 2019

Mechanisms that regulate morphogenesis of a highly branched neuron in C. elegans.

Dev Biol 2019 07 17;451(1):53-67. Epub 2019 Apr 17.

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA. Electronic address:

The shape of an individual neuron is linked to its function with axons sending signals to other cells and dendrites receiving them. Although much is known of the mechanisms for axonal outgrowth, the striking complexity of dendritic architecture has hindered efforts to uncover pathways that direct dendritic branching. Here we review the results of an experimental strategy that exploits the power of genetic analysis and live cell imaging of the PVD sensory neuron in C. elegans to reveal key molecular drivers of dendrite morphogenesis.
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http://dx.doi.org/10.1016/j.ydbio.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755292PMC
July 2019

Empyema Due to Thoracic Migrating Appendicolith.

Indian Pediatr 2018 07;55(7):603-604

Department of Paediatrics, CHILDS Trust Medical Research Foundation, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India.

Background: Retained appendicolith following appendicectomy, and can cause recurrent abscess in the abdomen and retroperitoneum.

Case Characteristics: 11-yr-old boy who presented with subpulmonic abscess and pneumonia following appendicectomy for perforated appendicitis.

Observation: Thoracotomy revealed a thick walled subpulmonic abscess surrounding an appendicolith along with a rent in the posterolateral aspect of the diaphragm.

Message: In children presenting with pus collections and a history of recent appendicectomy, the possibility of a migrating appendicolith should be considered.
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July 2018

Control of Growth Cone Polarity, Microtubule Accumulation, and Protrusion by UNC-6/Netrin and Its Receptors in .

Genetics 2018 09 25;210(1):235-255. Epub 2018 Jul 25.

Program in Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66046

UNC-6/Netrin has a conserved role in dorsal-ventral axon guidance, but the cellular events in the growth cone regulated by UNC-6/Netrin signaling during outgrowth are incompletely understood. Previous studies showed that, in growth cones migrating away from UNC-6/Netrin, the receptor UNC-5 regulates growth cone polarity, as observed by polarized F-actin, and limits the extent of growth cone protrusion. It is unclear how UNC-5 inhibits protrusion, and how UNC-40 acts in concert with UNC-5 to regulate polarity and protrusion. New results reported here indicate that UNC-5 normally restricts microtubule (MT) + end accumulation in the growth cone. Tubulin mutant analysis and colchicine treatment suggest that stable MTs are necessary for robust growth cone protrusion. Thus, UNC-5 might inhibit protrusion in part by restricting growth cone MT accumulation. Previous studies showed that the UNC-73/Trio Rac GEF and UNC-33/CRMP act downstream of UNC-5 in protrusion. Here, we show that UNC-33/CRMP regulates both growth cone dorsal asymmetric F-actin accumulation and MT accumulation, whereas UNC-73/Trio Rac GEF activity only affects F-actin accumulation. This suggests an MT-independent mechanism used by UNC-5 to inhibit protrusion, possibly by regulating lamellipodial and filopodial actin. Furthermore, we show that UNC-6/Netrin and the receptor UNC-40/DCC are required for excess protrusion in mutants, but not for loss of F-actin asymmetry or MT + end accumulation, indicating that UNC-6/Netrin and UNC-40/DCC are required for protrusion downstream of, or in parallel to, F-actin asymmetry and MT + end entry. F-actin accumulation might represent a polarity mark in the growth cone where protrusion will occur, and not protrusive lamellipodial and filopodial actin Our data suggest a model in which UNC-6/Netrin first polarizes the growth cone via UNC-5, and then regulates protrusion based upon this polarity (the polarity/protrusion model). UNC-6/Netrin inhibits protrusion ventrally via UNC-5, and stimulates protrusion dorsally via UNC-40, resulting in dorsally-directed migration. The polarity/protrusion model represents a novel conceptual paradigm in which to understand axon guidance and growth cone migration away from UNC-6/Netrin.
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http://dx.doi.org/10.1534/genetics.118.301234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116952PMC
September 2018

Neuronal Fat and Dendrite Morphogenesis: The Goldilocks Effect.

Trends Neurosci 2018 05 13;41(5):250-252. Epub 2018 Mar 13.

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240-1104, USA. Electronic address:

Two recent studies by Meltzer et al. and Ziegler et al. use Drosophila larvae to demonstrate that cell-autonomous regulation of lipid biosynthesis defines the complexity and function of highly branched nociceptive neurons. Their findings show that lipid biosynthesis in the neuron is fine-tuned for optimal dendrite morphology and sensitivity.
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http://dx.doi.org/10.1016/j.tins.2018.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924613PMC
May 2018

Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.

Dev Biol 2017 12 13;432(2):248-257. Epub 2017 Oct 13.

Vanderbilt University, 3120 MRB III, Nashville, TN 37240-7935, USA. Electronic address:

The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches.
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http://dx.doi.org/10.1016/j.ydbio.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714649PMC
December 2017

SDN-1/Syndecan Acts in Parallel to the Transmembrane Molecule MIG-13 to Promote Anterior Neuroblast Migration.

G3 (Bethesda) 2015 May 28;5(8):1567-74. Epub 2015 May 28.

Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045

The Q neuroblasts in Caenorhabditis elegans display left-right asymmetry in their migration, with QR and descendants on the right migrating anteriorly, and QL and descendants on the left migrating posteriorly. Initial QR and QL migration is controlled by the transmembrane receptors UNC-40/DCC, PTP-3/LAR, and the Fat-like cadherin CDH-4. After initial migration, QL responds to an EGL-20/Wnt signal that drives continued posterior migration by activating MAB-5/Hox activity in QL but not QR. QR expresses the transmembrane protein MIG-13, which is repressed by MAB-5 in QL and which drives anterior migration of QR descendants. A screen for new Q descendant AQR and PQR migration mutations identified mig-13 as well as hse-5, the gene encoding the glucuronyl C5-epimerase enzyme, which catalyzes epimerization of glucuronic acid to iduronic acid in the heparan sulfate side chains of heparan sulfate proteoglycans (HSPGs). Of five C. elegans HSPGs, we found that only SDN-1/Syndecan affected Q migrations. sdn-1 mutants showed QR descendant AQR anterior migration defects, and weaker QL descendant PQR migration defects. hse-5 affected initial Q migration, whereas sdn-1 did not. sdn-1 and hse-5 acted redundantly in AQR and PQR migration, but not initial Q migration, suggesting the involvement of other HSPGs in Q migration. Cell-specific expression studies indicated that SDN-1 can act in QR to promote anterior migration. Genetic interactions between sdn-1, mig-13, and mab-5 suggest that MIG-13 and SDN-1 act in parallel to promote anterior AQR migration and that SDN-1 also controls posterior migration. Together, our results indicate previously unappreciated complexity in the role of multiple signaling pathways and inherent left-right asymmetry in the control of Q neuroblast descendant migration.
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http://dx.doi.org/10.1534/g3.115.018770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528313PMC
May 2015

The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP.

Development 2014 Nov;141(22):4395-405

Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA

UNC-6/Netrin is a conserved axon guidance cue that can mediate both attraction and repulsion. We previously discovered that attractive UNC-40/DCC receptor signaling stimulates growth cone filopodial protrusion and that repulsive UNC-40-UNC-5 heterodimers inhibit filopodial protrusion in C. elegans. Here, we identify cytoplasmic signaling molecules required for UNC-6-mediated inhibition of filopodial protrusion involved in axon repulsion. We show that the Rac-like GTPases CED-10 and MIG-2, the Rac GTP exchange factor UNC-73/Trio, UNC-44/Ankyrin and UNC-33/CRMP act in inhibitory UNC-6 signaling. These molecules were required for the normal limitation of filopodial protrusion in developing growth cones and for inhibition of growth cone filopodial protrusion caused by activated MYR::UNC-40 and MYR::UNC-5 receptor signaling. Epistasis studies using activated CED-10 and MIG-2 indicated that UNC-44 and UNC-33 act downstream of the Rac-like GTPases in filopodial inhibition. UNC-73, UNC-33 and UNC-44 did not affect the accumulation of full-length UNC-5::GFP and UNC-40::GFP in growth cones, consistent with a model in which UNC-73, UNC-33 and UNC-44 influence cytoskeletal function during growth cone filopodial inhibition.
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http://dx.doi.org/10.1242/dev.110437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302909PMC
November 2014

The fat-like cadherin CDH-4 acts cell-non-autonomously in anterior-posterior neuroblast migration.

Dev Biol 2014 Aug 19;392(2):141-52. Epub 2014 Jun 19.

Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, The University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, United States. Electronic address:

Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In Caenorhabditis elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL-20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP-3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non-autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts.
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http://dx.doi.org/10.1016/j.ydbio.2014.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136450PMC
August 2014

Transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 control anterior-posterior neuroblast migration with left-right functional asymmetry in Caenorhabditis elegans.

Genetics 2012 Dec 10;192(4):1373-88. Epub 2012 Oct 10.

Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left-right axis. Initial migration is independent of a Wnt signal that controls later anterior-posterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other's role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left-right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration.
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http://dx.doi.org/10.1534/genetics.112.145706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512145PMC
December 2012

Ureteral damage during appendicectomy.

J Pediatr Surg 2010 Nov;45(11):e11-3

Department of Paediatric Surgery, University Hosp of Wales, CF 14 4XW Cardiff, Wales, UK.

A case of right ureteric damage in a 7-year-old boy who underwent appendicectomy is described. Ultrasound, magnetic resonance urography, nephrostogram, and retrograde ureterogram were helpful in defining the nature and extent of the lesion. He underwent staged procedures of percutaneous nephrostomy, elective resection and reconstruction of midureteral segment, and subsequent removal of double J stent and made a smooth recovery. Ureteric injuries, although rare, have serious consequences. A high index of suspicion is essential for diagnosis. Management is influenced by site, type, extent, and mechanism of injury, as well as the timing of detection.
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http://dx.doi.org/10.1016/j.jpedsurg.2010.07.015DOI Listing
November 2010

A knotted problem.

Arch Dis Child 2011 Jan 26;96(1):90. Epub 2010 Oct 26.

Department of Paediatric Surgery, University Hospital of Wales, Heath Park, Cardiff, UK.

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http://dx.doi.org/10.1136/adc.2010.198556DOI Listing
January 2011

Horseshoe kidney: retroperitoneoscopic nephrectomy.

J Pediatr Urol 2007 Apr 15;3(2):159-61. Epub 2006 Sep 15.

Department of Paediatric Surgery, Birmingham Children's Hospital NHS Trust, Steelhouse Lane, Birmingham B4 6NH, UK.

The ideal approach for nephrectomy in the child with horseshoe kidney is debatable. We present two such children who underwent nephrectomy by a retroperitoneoscopic approach. Recognition of its anatomical variation is essential in the management of horseshoe kidney. Surgery is high risk, even using a traditional open procedure, because loss of the remaining half of the kidney is catastrophic.
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http://dx.doi.org/10.1016/j.jpurol.2006.07.004DOI Listing
April 2007

Antenatal rectal perforation presenting in the neonate.

Pediatr Surg Int 2008 May 26;24(5):601-3. Epub 2008 Jan 26.

Department of Paediatric Surgery, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK.

Perforation of the rectum in the antenatal period is extremely rare. Three cases have been reported worldwide. Its aetiology and pathophysiology are poorly understood. Rapid recognition by its classical signs is mandatory as delay in diagnosis leads to serious morbidity. We report a fourth case, and make recommendations regarding management.
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http://dx.doi.org/10.1007/s00383-007-2080-xDOI Listing
May 2008

Evolving experience with video-assisted thoracic surgery in congenital cystic lung lesions in a British pediatric center.

J Pediatr Surg 2007 Jul;42(7):1243-50

Department of Paediatric Surgery, Birmingham Children's Hospital NHS Trust, B4 6NH Birmingham, UK.

Background/purpose: Video-assisted thoracic surgery (VATS) is increasingly used for the resection of congenital cystic lung lesions (CLLs). This study aimed to evaluate the efficacy of VATS and its outcome in both antenatally and postnatally detected CLLs.

Methods: Forty-six patients managed during 2000-2005 were studied. Demographics, investigations, operative details, and outcome data were collected and evaluated. Patients were divided into 3 groups for analysis.

Results: Antenatally diagnosed (groups I and II, n = 35): group I (20) had VATS at 20 months median (range, 16-35 months). Video-assisted thoracic surgery was successful in 14 of 20 (70%), notably in all cases of extralobar sequestrations and foregut duplication cysts. Inadequate vision/lung collapse and technical difficulties were the main reasons for conversion to open thoracotomy. Group II (n = 15) was considered unsuitable for VATS because of neonatal symptoms (6 congenital cystic adenomatoid malformations of the lung [CCAMs]) and/or large size/inexperience (5 CCAMs, 4 sequestrations) and had elective thoracotomy at 8 months median (range, 6 days-20 months). Postnatally diagnosed (group III, n = 11): 3 CCAMs, 6 duplications, and 2 sequestrations were diagnosed because of recurrent chest infection (8) or stridor (2), or incidentally (1) at 8 years median (range, 1.2-14 years). Video-assisted thoracic surgery was successful in 3 foregut duplications. A duplication and an intralobar sequestration were converted; open thoracotomy was performed in others because of previous recurrent pneumonic episodes. Postoperative pain and hospital stay were significantly less (P < .001) in successful VATS resection: median of 2 days (range, 1-7 days) compared with thoracotomy median of 6 days (range, 4-20 days).

Conclusions: Video-assisted thoracic surgery is a safe and effective option for asymptomatic congenital CLLs. It is anticipated that more successful CCAM resections using VATS will occur in the future as our technical ability improves.
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http://dx.doi.org/10.1016/j.jpedsurg.2007.02.016DOI Listing
July 2007