Publications

Journal Article
Dong, J, MacAlister CA, Bergmann DC.  2009.  BASL controls asymmetric cell division in Arabidopsis.. Cell. 137(7):1320-1330.
Zhang, Y, Wang P, Shao W, Zhu J-K, Dong J.  2015.  The BASL Polarity Protein Controls a MAPK Signaling Feedback Loop in Asymmetric Cell Division.. Dev Cell. doi: 10.1016/j.devcel.2015.02.022.
Ebright, RH, Wong JR, Chen LB.  1986.  Binding of 2-hydroxybenzo(a)pyrene to estrogen receptors in rat cytosol.. Cancer research. 46(5):2349-51. Abstract
The potent carcinogen 2-hydroxybenzo(a)pyrene (2-OH-BP) competes for binding to the estrogen receptor in the cytosol of rat uterus and liver. The dissociation constant (K1) for this interaction is congruent to 2 X 10(-5) M. In contrast, 4-hydroxybenzo(a)pyrene does not bind to the estrogen receptor; 1-hydroxybenzo(a)pyrene, 5-hydroxybenzo(a)pyrene, 6-hydroxybenzo(a)pyrene, and 12-hydroxybenzo(a)pyrene bind less tightly than does 2-OH-BP. These five chemicals are not carcinogenic. We suggest that the estrogen receptor may mediate the carcinogenic effect of 2-OH-BP or of related chemicals. One possibility is that the receptor might convey 2-OH-BP to specific sites in DNA.
Ebright, RH, Connell ND.  2002.  Bioweapon agents: more access means more risk.. Nature. 415(6870):364.
Piomelli, S, Corash L, Corash MB, Seaman C, Mushak P, Glover B, Padgett R.  1980.  Blood lead concentrations in a remote Himalayan population. Science (New York, NY). 210:1135-7. AbstractWebsite
The lead content in the air at the foothills of the Himalayas in Nepal was found to be negligible. The concentration of lead in the blood of 103 children and adults living in this region was found to average 3.4 micrograms per deciliter, a level substantially lower than that found in industrialized populations.
Suzuki, Y, Yandell M, Roy P, Krishna S, Savage-Dunn C, Ross R, Padgett R, Wood W.  1999.  A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans. Development (Cambridge, England). 126:241-250.. Abstract
We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes. Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures. Conversely, dbl-1 overexpression causes markedly increased body size and partly complementary male tail phenotypes, indicating that DBL-1 acts as a dose-dependent regulator of these processes. Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand. Our study of the dbl-1 expression pattern suggests a role for neuronal cells in global size regulation as well as male tail patterning.
Kirilly, D, Spana EP, Perrimon N, Padgett RW, Xie T.  2005.  BMP signaling is required for controlling somatic stem cell self-renewal in the Drosophila ovary. Developmental cell. 9:651-62. AbstractWebsite
BMP signaling is essential for promoting self-renewal of mouse embryonic stem cells and Drosophila germline stem cells and for repressing stem cell proliferation in the mouse intestine and skin. However, it remains unknown whether BMP signaling can promote self-renewal of adult somatic stem cells. In this study, we show that BMP signaling is necessary and sufficient for promoting self-renewal and proliferation of somatic stem cells (SSCs) in the Drosophila ovary. BMP signaling is required in SSCs to directly control their maintenance and division, but is dispensable for proliferation of their differentiated progeny. Furthermore, BMP signaling is required to control SSC self-renewal, but not survival. Moreover, constitutive BMP signaling prolongs the SSC lifespan. Therefore, our study clearly demonstrates that BMP signaling directly promotes SSC self-renewal and proliferation in the Drosophila ovary. Our work further suggests that BMP signaling could promote self-renewal of adult stem cells in other systems.
Gleason, RJ, Akintobi AM, Grant BD, Padgett RW.  2014.  BMP signaling requires retromer-dependent recycling of the type I receptor. Proc. Natl. Acad. Sci., USA . 10.1073/pnas.1319947111
Carrieri, D, Momot D, Brasg IA, Ananyev GM, Lenz O, Bryant DA, Dismukes CG.  2011.  Boosting autofermentation rates and product yields with sodium stress cycling: Application to renewable fuel production by cyanobacteria. Appl. Environ. Microbiol.. :AEM.00975-10%Uhttp://aem.asm.org/cgi/content/abstract/AEM.00975-10v1. Abstract
Sodium concentration cycling was examined as a new strategy for redistributing carbon storage products and increasing autofermentative product yields following photosynthetic carbon fixation in the cyanobacterium Arthrospira (Spirulina) maxima. The salt-tolerant hyper-carbonate strain CS-328 was grown in a medium containing 0.24 to 1.24 M sodium, resulting in increased biosynthesis of soluble carbohydrates up to 50% of the dry weight at 1.24 M sodium. Hypoionic stress during dark anaerobic metabolism (autofermentation) was induced by resuspending filaments in low sodium (bi)carbonate buffer (0.21 M), which resulted in accelerated autofermentation rates. For cells grown in 1.24 M NaCl, the fermentative yields of acetate, ethanol and formate increase substantially to 0.75, 1.56 and 1.54 mmol/(gDW*day), respectively (36, 121, and 6-fold increases in rate relative to cells grown in 0.24 M NaCl). Catabolism of endogenous carbohydrate increased by approximately 2-fold upon hypoionic stress. For cultures grown at all salt concentrations, hydrogen was produced but its yield did not correlate with increased catabolism of soluble carbohydrates. Instead, ethanol excretion becomes a preferred route for fermentative NADH reoxidation together with intraceullar accumulation of reduced products of acetyl-CoA formation when cells are hypoionically stressed. In the absence of hypoionic stress, hydrogen production is a major beneficial pathway for NAD+ regeneration without wasting carbon intermediates such as ethanol derived from acetyl-CoA. This switch presumably improves the overall cellular economy by retaining carbon within the cell until aerobic conditions return and the acetyl unit can be used for biosynthesis or oxidized via respiration for much greater energy return.
Chatterjee, M, Tabi Z, Galli M, Malcomber S, Buck A, Muszynski M, Gallavotti A.  2014.  The boron efflux transporter ROTTEN EAR is required for maize inflorescence development and fertility. Plant Cell. (26):2962-2977. AbstractWebsite
Although boron has a relatively low natural abundance, it is an essential plant micronutrient. Boron deficiencies cause major crop losses in several areas of the world, affecting reproduction and yield in diverse plant species. Despite the importance of boron in crop productivity, surprisingly little is known about its effects on developing reproductive organs. We isolated a maize (Zea mays) mutant, called rotten ear (rte), that shows distinct defects in vegetative and reproductive development, eventually causing widespread sterility in its inflorescences, the tassel and the ear. Positional cloning revealed that rte encodes a membrane-localized boron efflux transporter, co-orthologous to the Arabidopsis thaliana BOR1 protein. Depending on the availability of boron in the soil, rte plants show a wide range of phenotypic defects that can be fully rescued by supplementing the soil with exogenous boric acid, indicating that rte is crucial for boron transport into aerial tissues. rte is expressed in cells surrounding the xylem in both vegetative and reproductive tissues and is required for meristem activity and organ development.We show that low boron supply to the inflorescences results in widespread defects in cell and cell wall integrity, highlighting the structural importance of boron in the formation of fully fertile reproductive organs.
Irvine, KD, Rauskolb C.  2001.  Boundaries in development: formation and function. Annual Review of Cell and Developmental Biology. 17:189-214. AbstractWebsite
Developing organisms may contain billions of cells destined to differentiate in numerous different ways. One strategy organisms use to simplify the orchestration of development is the separation of cell populations into distinct functional units. Our expanding knowledge of boundary formation and function in different systems is beginning to reveal general principles of this process. Fields of cells are subdivided by the interpretation of morphogen gradients, and these subdivisions are then maintained and refined by local cell-cell interactions. Sharp and stable separation between cell populations requires special mechanisms to keep cells segregated, which in many cases appear to involve the regulation of cell affinity. Once cell populations become distinct, specialized cells are often induced along the borders between them. These boundary cells can then influence the patterning of surrounding cells, which can result in progressively finer subdivisions of a tissue. Much has been learned about the signaling pathways that establish boundaries, but a key challenge for the future remains to elucidate the cellular and molecular mechanisms that actually keep cell populations separated.
Barr, MM, Silva M, Haas LA, Morsci NS, Nguyen KCQ, Hall DH, Barr MM.  2014.  C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication.. Current biology : CB. 24(5):519-25. Abstract
Cells release extracellular vesicles (ECVs) that play important roles in intercellular communication and may mediate a broad range of physiological and pathological processes. Many fundamental aspects of ECV biogenesis and signaling have yet to be determined, with ECV detection being a challenge and obstacle due to the small size (100 nm) of the ECVs. We developed an in vivo system to visualize the dynamic release of GFP-labeled ECVs. We show here that specific Caenorhabdidits elegans ciliated sensory neurons shed and release ECVs containing GFP-tagged polycystins LOV-1 and PKD-2. These ECVs are also abundant in the lumen surrounding the cilium. Electron tomography and genetic analysis indicate that ECV biogenesis occurs via budding from the plasma membrane at the ciliary base and not via fusion of multivesicular bodies. Intraflagellar transport and kinesin-3 KLP-6 are required for environmental release of PKD-2::GFP-containing ECVs. ECVs isolated from wild-type animals induce male tail-chasing behavior, while ECVs isolated from klp-6 animals and lacking PKD-2::GFP do not. We conclude that environmentally released ECVs play a role in animal communication and mating-related behaviors.
Maduzia, LL, Roberts AF, Wang H, Lin X, Chin LJ, Zimmerman CM, Cohen S, Feng X-H, Padgett RW.  2005.  C. elegans serine-threonine kinase KIN-29 modulates TGFβ signaling and regulates body size formation. BMC developmental biology. 5:8. AbstractWebsite
BACKGROUND: In C. elegans there are two well-defined TGFbeta-like signaling pathways. The Sma/Mab pathway affects body size morphogenesis, male tail development and spicule formation while the Daf pathway regulates entry into and exit out of the dauer state. To identify additional factors that modulate TGFbeta signaling in the Sma/Mab pathway, we have undertaken a genetic screen for small animals and have identified kin-29. RESULTS: kin-29 encodes a protein with a cytoplasmic serine-threonine kinase and a novel C-terminal domain. The kinase domain is a distantly related member of the EMK (ELKL motif kinase) family, which interacts with microtubules. We show that the serine-threonine kinase domain has in vitro activity. kin-29 mutations result in small animals, but do not affect male tail morphology as do several of the Sma/Mab signal transducers. Adult worms are smaller than the wild-type, but also develop more slowly. Rescue by kin-29 is achieved by expression in neurons or in the hypodermis. Interaction with the dauer pathway is observed in double mutant combinations, which have been seen with Sma/Mab pathway mutants. We show that kin-29 is epistatic to the ligand dbl-1, and lies upstream of the Sma/Mab pathway target gene, lon-1. CONCLUSION: kin-29 is a new modulator of the Sma/Mab pathway. It functions in neurons and in the hypodermis to regulate body size, but does not affect all TGFbeta outputs, such as tail morphogenesis.
Barr, MM.  2005.  Caenorhabditis Elegans as a Model to Study Renal Development and Disease: sexy Cilia. J Am Soc Nephrol. 16:305-312. Abstract
The nematode Caenorhabditis elegans has no kidney per se, yet ``the worm'' has proved to be an excellent model to study renal-related issues, including tubulogenesis of the excretory canal, membrane transport and ion channel function, and human genetic diseases including autosomal dominant polycystic kidney disease (ADPKD). The goal of this review is to explain how C. elegans has provided insight into cilia development, cilia function, and human cystic kidney diseases.
Savage, C, Das P, Finelli A, Townsend S, Sun C, Baird S, Padgett R.  1996.  Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc Natl Acad Sci U S A. 93:790-794. AbstractWebsite
Although transforming growth factor beta (TGF-beta) superfamily ligands play critical roles in diverse developmental processes, how cells transduce signals from these ligands is still poorly understood. Cell surface receptors for these ligands have been identified, but their cytoplasmic targets are unknown. We have identified three Caenorhabditis elegans genes, sma-2, sma-3, and sma-4, that have mutant phenotypes similar to those of the TGF-beta-like receptor gene daf-4, indicating that they are required for daf-4-mediated developmental processes. We show that sma-2 functions in the same cells as daf-4, consistent with a role in transducing signals from the receptor. These three genes define a protein family, the dwarfins, that includes the Mad gene product, which participates in the decapentaplegic TGF-beta-like pathway in Drosophila [Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. (1995) Genetics 139, 1347-1358]. The identification of homologous components of these pathways in distantly related organisms suggests that dwarfins may be universally required for TGF-beta-like signal transduction. In fact, we have isolated highly conserved dwarfins from vertebrates, indicating that these components are not idiosyncratic to invertebrates. These analyses suggest that dwarfins are conserved cytoplasmic signal transducers.
Jauregui, AR, Nguyen KCQ, Hall DH, Barr MM.  2008.  The Caenorhabditis Elegans Nephrocystins act as Global Modifiers of Cilium Structure. J Cell Biol. 180:973-988. Abstract
Nephronophthisis (NPHP) is the most common genetic cause of end-stage renal disease in children and young adults. In Chlamydomonas reinhardtii, Caenorhabditis elegans, and mammals, the NPHP1 and NPHP4 gene products nephrocystin-1 and nephrocystin-4 localize to basal bodies or ciliary transition zones (TZs), but their function in this location remains unknown. We show here that loss of C. elegans NPHP-1 and NPHP-4 from TZs is tolerated in developing cilia but causes changes in localization of specific ciliary components and a broad range of subtle axonemal ultrastructural defects. In amphid channel cilia, nphp-4 mutations cause B tubule defects that further disrupt intraflagellar transport (IFT). We propose that NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary access of the IFT machinery, axonemal structural components, and signaling molecules, and that perturbing this balance results in cell type-specific phenotypes.
Patton, JR, Padgett RW.  2003.  Caenorhabditis elegans pseudouridine synthase 1 activity in vivo: tRNA is a substrate, but not U2 small nuclear RNA. The Biochemical journal. 372:595-602. AbstractWebsite
The formation of pseudouridine (Psi) from uridine is post-transcriptional and catalysed by pseudouridine synthases, several of which have been characterized from eukaryotes. Pseudouridine synthase 1 (Pus1p) has been well characterized from yeast and mice. In yeast, Pus1p has been shown to have dual substrate specificity, modifying uridines in tRNAs and at position 44 in U2 small nuclear RNA (U2 snRNA). In order to study the in vivo activity of a metazoan Pus1p, a knockout of the gene coding for the homologue of Pus1p in Caenorhabditis elegans was obtained. The deletion encompasses the first two putative exons and includes the essential aspartate that is required for activity in truA pseudouridine synthases. The locations of most modified nucleotides on small RNAs in C. elegans are not known, and the positions of Psi were determined on four tRNAs and U2 snRNA. The uridine at position 27 of tRNA(Val) (AAC), a putative Pus1p-modification site, was converted into Psi in the wild-type worms, but the tRNA(Val) (AAC) from mutant worms lacked the modification. Psi formation at positions 13, 32, 38 and 39, all of which should be modified by other pseudouridine synthases, was not affected by the loss of Pus1p. The absence of Pus1p in C. elegans had no effect on the modification of U2 snRNA in vivo, even though worm U2 snRNA has a Psi at position 45 (the equivalent of yeast U2 snRNA position 44) and at four other positions. This result was unexpected, given the known dual specificity of yeast Pus1p.
Gumienny, TL, Macneil L, Zimmerman CM, Wang H, Chin L, Wrana JL, Padgett RW.  2010.  Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling. PLoS genetics. 6:e1000963. AbstractWebsite
Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP-like receptor signaling. SMA-10 acts genetically in a BMP-like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors.
Bartlett, JE, Baranov SV, Ananyev GM, Dismukes GC.  2008.  Calcium controls the assembly of the photosynthetic water-oxidizing complex: a cadmium(II) inorganic mutant of the Mn4Ca core. Philosophical Transactions of the Royal Society B-Biological Sciences. 363:1253-1261. AbstractWebsite
Perturbation of the catalytic inorganic core (Mn4Ca1OxCly) of the photosystem II-water-oxidizing complex (PSII-WOC) isolated from spinach is examined by substitution of Ca2+ with cadmium(II) during core assembly. Cd2+ inhibits the yield of reconstitution of O-2-evolution activity, called photoactivation, starting from the free inorganic cofactors and the cofactor-depleted apo-WOC-PSII complex. Ca2+ affinity increases following photooxidation of the first Mn2+ to Mn3+ bound to the 'high-affinity' site. Ca2+ binding occurs in the dark and is the slowest overall step of photoactivation (IM1/IM*(1) -> step). Cd2+ competitively blocks the binding of Ca2+ to its functional site with 10-to 30-fold higher affinity, but does not influence the binding of Mn2+ to its high-affinity site. By contrast, even 10-fold higher concentrations of Cd2+ have no effect on O-2-evolution activity in intact PSII-WOC. Paradoxically, Cd2+ both inhibits photoactivation yield, while accelerating the rate of photoassembly of active centres 10-fold relative to Ca2+. Cd2+ increases the kinetic stability of the photooxidized Mn3+ assembly intermediate(s) by twofold (mean lifetime for dark decay). The rate data provide evidence that Cd2+ binding following photooxidation of the first Mn3+, IM1/IM*(1), causes three outcomes: (i) a longer intermediate lifetime that slows IM1 decay to IM0 by charge recombination, (ii) 10-fold higher probability of attaining the degrees of freedom (either or both cofactor and protein d.f.) needed to bind and photooxidize the remaining 3 Mn2+ that form the functional cluster, and (iii) increased lability of Cd2+ following Mn-4 cluster assembly results in (re) exchange of Cd2+ by Ca2+ which restores active O-2-evolving centres. Prior EPR spectroscopic data provide evidence for an oxo-bridged assembly intermediate, Mn3+ (mu-O2-) Ca2+, for IM*(1). We postulate an analogous inhibited intermediate with Cd2+ replacing Ca2+.
Singaravelu, G, Singson A.  2013.  Calcium signaling surrounding fertilization in the nematode Caenorhabditis elegans. Cell Calcium. 53:2-9. Abstract
Calcium plays a prominent role during fertilization in many animals. This review focuses on roles of Ca(2+) during the events around fertilization in the model organism, Caenorhabditis elegans. Specifically, the role of Ca(2+) in sperm, oocytes and the surrounding somatic tissues during fertilization will be discussed, with the focus on sperm activation, meiotic maturation of oocytes, ovulation, sperm-egg interaction and fertilization.
Rongo, C, Kaplan JM.  1999.  CaMKII regulates the density of central glutamatergic synapses in vivo. Nature. 402:195-9. AbstractWebsite
Synaptic connections undergo a dynamic process of stabilization or elimination during development, and this process is thought to be critical in memory and learning and in establishing the specificity of synaptic connections. The type II calcium- and calmodulin-dependent protein kinase (CaMKII) has been proposed to be pivotal in regulating synaptic strength and in maturation of synapses during development. Here we describe how CaMKII regulates the formation of central glutamatergic synapses in Caenorhabditis elegans. During larval development, the density of ventral nerve cord synapses containing the GLR-1 glutamate receptor is held constant despite marked changes in neurite length. The coupling of synapse number to neurite length requires both CaMKII and voltage-gated calcium channels. CaMKII regulates GLR-1 by at least two distinct mechanisms: regulating transport of GLR-1 from cell bodies to neurites; and regulating the addition or maintenance of GLR-1 to postsynaptic elements.