We utilize the small nematode Caenorhabditis elegans as a genetic model for much of our work. This organism has similar genes in type and number as mammals, including humans, and has been instrumental in discovering many cellular mechanisms that control animal (including human) development and diseases. In addition, the nervous system of C. elegans is understood better than any other nervous system, providing a unique opportunity to study basic aspects of neuronal development and function. We have three major projects in the lab.

Project I: Understanding dendrite patterning

Neurons or nerve cells are the basic building blocks of the nervous system. They contain structures that receive information from the environment or other neurons. These receiving structures are termed dendrites and are often elaborately branched processes that can resemble trees. On the other hand, the parts of neurons that transmit information to other neurons are processes called axons. Through the synaptic connections between an axon with the dendrites of another neuron(s) a neural network can be formed. Such networks in the brain are crucial for all aspects of animal behavior.

In many neurological conditions, such as autism spectrum disorders, schizophrenia and syndromes of intellectual disability the formation of dendrites is impaired or defective with sometimes less and disorganized dendrite structures and sometimes excessively branched dendrites. In one project, we seek to understand the basic biologic mechanisms that control dendrite patterning, because we believe that we need to understand these mechanisms first before we can start developing therapeutic approaches.  

Project II: Understanding Neuronal rewiring during learning and memory

In a second project, we are investigating development and function of the connectome, i.e. the hardwiring of the nervous system. The neurons in an animal form a neural network by using for communication between nerve cells chemical connections (aka synapses) and electrical connections (aka GAP junctions). The nematode C. elegans remains the only animal for which we have the complete qualitative and quantitative connectivity of the nervous systems for both sexes of the animal. We are interested in how an animal's experience (e.g. during learning) can influence and change synaptic connectivity, i.e. the neural networks. To this end, we have developed methods to visualize cell-specific synaptic connections in live animals. We are now using a combination of genetic, behavioral, and imaging approaches to test how specific synaptic connections change in response to the environment and experience, and which genes mediate these processes.

Project III: Understanding and harnessing the molecular diversity of glycosaminoglycans.

In a third project, we are studying the role of proteoglycans, e.g. heparan sulfate (HS) proteoglycans in development an disease. We are asking how specific modification patterns of the polysaccharide HS determine the path of developing axons. For instance, we have shown that distinct modification patterns in HS serve specific and instructive functions during neural development leading us to formulate the ‘HS code’ hypothesis. We propose that defined combinations of modifications in the sugars of HS contain information and generate a molecular map that shapes animal development. In a multidisciplinary collaborative approach with the laboratories of Drs Almo, Steidl and Zheng, we are leveraging the molecular diversity of the HS code to define cells in mammals including mice and human in novel ways in both healthy and diseased states.

Salazar C.J., Díaz-Balzac C.A., Wang Y., Rahman M., Grant B.D., and Bülow H.E. (2023) RABR-1, an atypical Rab-related GTPase cell non-autonomously restricts somatosensory dendrite branching. GENETICS, iyae113, published online on July 19, 2024 as https://doi.org/10.1093/genetics/iyae113.

Heiman M.G. & Bülow H.E. (2024) Dendrite Morphogenesis in Caenorhabditis elegans, WormBook, GENETICS, iyae056, published online on May 24, 2024 as https://doi.org/10.1093/genetics/iyae056. PMCID: PMC11151937.

Piszczatowski R.T., Bülow H.E., Steidl U.* (2024) Heparan Sulfate and Heparan Sulfate Proteoglycans in Hematopoiesis, BLOOD, published online on March 25, 2024 as https://doi.org/10.1182/blood.2023022736. PMCID: TBD.

Tang L.T. *, Lee G.L. *, Cook S.C., Ho J., Potter C.W., and Bülow H.E. (2023) Anatomical restructuring of a lateralized neural circuit during associative learning by asymmetric insulin signaling, Current Biology, 33:1–16, published online on August 16 as https://doi.org/10.1016/j.cub.2023.07.041. PMCID: PMC10639090. 

Ramirez-Suarez N.J., Belalcazar H.M., Rahman M., Trivedi M., Tang L.T.H., and Bülow H.E. (2023) Convertase-dependent regulation of a membrane tethered ligand in trans tunes dendrite adhesion, Development, Sept. 18, 150, dev201208, published online on August 10 ashttps://doi.org/10.1242/dev.201208. PMCID: PMC10546877.

Rahman M., Ramirez-Suarez N.J., Diaz-Balzac C.A., and Bülow H.E. (2022) Specific N-glycan regulate an extracellular adhesion complex during somatosensory dendrite patterning, EMBO Reports, May 19,e5416310; https://doi.org/10.15252/embr.202154163.

Piszczatowski R.T. ^#, Schwenger E. ^#, Sundaravel S, Stein C.M., Liu Y., Stanley P., Verma A., Zheng D., Seidel R.D., Almo S.C., Townley R.A.^*, Bülow H.E.^*, Steidl U.^* (2022) A glycan-based approach to cell characterization and isolation: hematopoiesis as a paradigm, J. Exp. Med., Nov 7; 219(11): e20212552, published online on September 6, 2022 as  e20212552. ^# contributed equally, * corresponding authors. https://doi.org/10.1084/jem.20212552. PMCID: PMC9455685.

Zhou X., Vachon C., Cizeron M., Romatif O., Bülow H.E., Jospin M., Bessereau J.L. (2021) The HSPG Syndecan is a core organizer of cholinergic synapses in C. elegans, J. Cell Biol., Sep 6;220(9), published online July 2, 2021 as https://doi.org/10.1083/jcb.202011144

Tang L.T.*, Trivedi M.*, Freund J., Salazar C.J., Lee G.L., Ramirez-Suarez N.J., Rahman M., Wang Y., Grant, B.D., Bülow H.E. (2021) The CATP-8/P5A-type ATPase is required for multiple aspects of neuronal patterning, PLoS Genetics, Jul 1;17(7):e1009475, published online July 1, 2021 as https://doi.org/10.1371/journal.pgen.1009475. PMCID: PMC8279360

Cizeron M., Granger L., Bülow H.E., Bessereau J.L. (2021) Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at C. elegans neuromuscular junctions, GENETICS, published online May 13, 2021 as https://doi.org/10.1093/genetics/iyab073. PMCID: PMC8864735.

Cook S.J., Jarrell T.A., Britten C., Wang Y., Bloniarz A.E., Yakovlev M.A., Nguyen K.C.Q., Tang L.TZ., Bayer E.A., Duerr J.S., Bülow H.E., Hobert O., Hall D.H. & Emmons S.W. (2019) Whole-animal connectomes of both Caenorhabditis elegans sexes, Nature, 571(7763):63-71, published online on July 3, 2019 as https://doi.org/10.1038/s41586-019-1352-7.

Tang L.TH.*, Díaz-Balzac C.A.*, Rahman M., Ramirez-Suarez N.J., Salzberg Y., Lázaro-Peña M.I., and Bülow H.E. (2019) TIAM-1/GEF can shape somatosensory dendrites independently of its GEF activity by regulating F-actin localization. eLife; 8:e38949 DOI: 10.7554/eLife.38949.

Ramirez-Suarez N.J., Belalcazar H.M., Salazar C.J., Beyaz B., Raja B., Nguyen K.C.Q., Celestrin K., Fredens J., Færgeman N.J., Hall D.H., and Bülow H.E. (2019) Axon-dependent patterning and maintenance of somatosensory dendritic arbors, Dev. Cell, 48:229-244, pii: S1534-5807(18)31083-9. published online on January 17, 2019 as https://doi.org/10.1016/j.devcel.2018.12.015.

Celestrin K., Díaz-Balzac C.A., Tang L.TZ., Ackley B.D., and  Bülow H.E. (2018) Four specific Ig domains in UNC-52/Perlecan function with NID-1/Nidogen during dendrite morphogenesis in Caenorhabditis elegans. Development, 145(10):dev158881, published online on May 14, 2018 as https://doi.org/10.1242/dev.158881.

Townley, R.A., Bülow H.E. (2018) Deciphering functional glycosaminoglycan motifs in development. Curr. Op. in Struct. Biol, 50:144-514, published online on March 23, 2018 as https://doi.org/10.1016/j.sbi.2018.03.011.

Saied-Santiago K., Bülow H.E. (2018) Diverse Roles for Glycosaminoglycans in Neural Patterning. Dev. Dyn., 247(1):54-74, published online on Jul 24, 2017 as https://doi.org/10.1002/dvdy.24555. 

Lázaro-Peña M.I., Díaz-Balzac C.A., Bülow H.E., and Emmons S.W. (2018) Heparan sulfate molecules mediate synapse formation and function of male mating neural circuits in C. elegans. GENETICS, 209(1):195-208, published online on March 20, 2018 as https://doi.org/10.1534/genetics.118.300837.

Saied-Santiago K., Townley R.A., Attonito J., da Cunha D.S., Tecle E., and Bülow H.E. (2017) Coordination of heparan sulfate proteoglycans with Wnt signaling to control cellular migrations and positioning in Caenorhabditis elegans. GENETICS, 206(4):1951-1967, published online on June 2, 2017 as https://doi.org/10.1534/genetics.116.198739.

Salzberg Y., Coleman, A., Celestrin K., Biederer T., Henis-Korenblit* S., and Bülow* H.E. (2017) Reduced insulin/insulin-like growth factor receptor signaling mitigates defective dendrite morphogenesis in mutants of the ER stress sensor IRE-1. PLoS Genetics, 13(1):e1006579. published online on January 24, 2017 as https://doi.org/10.1371/journal.pgen.1006579. * corresponding authors.

Díaz-Balzac C.A., Rahman M., Lázaro-Peña M.I., Martin Hernandez L.A., Salzberg Y., Aguirre-Chen C., Kaprielian Z., and Bülow H.E. (2016) Muscle- and skin-derived cues jointly orchestrate patterning of somatosensory dendrites. Current Biology, 26:1-9, published online on July 21 as http://dx.doi.org/10.1016/j.cub.2016.07.008.

Attreed, M., Saied-Santiago, K., and Bülow H.E. (2016) Conservation of anatomically restricted glycosaminoglycan structures in divergent nematode species.  Glycobiology, 26(8):862-870, published online on April 8, 2016 as https://doi.org/10.1093/glycob/cww037.

Díaz-Balzac C.A., Lázaro-Peña M.I., Ramos-Ortiz G.O., Bülow H.E. (2015) The Adhesion molecule KAL-1/anosmin-1 regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex. Cell Reports, 11:1–8, published online on May 21 as http://dx.doi.org/10.1016/j.celrep.2015.04.057.

Desbois M., Cook S.J., Emmons, S.W., and Bülow H.E. (2015) Directional trans-synaptic labeling of specific synaptic connections in live animals. GENETICS, 200(3):697-705,  published online on April 27, 2015 as https://doi.org/10.1534/genetics.115.177006.

Dong X, Shen K*, and Bülow H.E.* (2015) Intrinsic and extrinsic mechanisms of dendrite morphogenesis. Annu. Rev. Physiol., 77:18.1–18.30, published onilne on October 24, 2014 as https://doi.org/10.1146/annurev-physiol-021014-071746.  * corresponding authors

Salzberg Y., Ramirez-Suarez N.J., Bülow H.E. (2014) The Proprotein Convertase KPC-1/Furin Controls Brnahcing and Self-avoidance of Sensory Dendrites of Caenorhabditis elegans. PLoS Genetics, 10(9):e1004657. published online on September 18, 2014 as https://doi.org/10.1371/journal.pgen.1004657.

Díaz-Balzac C.A., Lázaro-Peña M.I., Tecle E., Gomez N., and Bülow H.E. (2014) Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in C. elegans. G3 (Bethesda), 2014 Aug 5. pii: g3.114.012591. Published online as  https://doi.org/10.1534/g3.114.012591.

Salzberg Y., Diaz-Balzac C.A., Ramirez-Suarez N.J., Attreed M., Tecle E., Desbois M., Kaprielian Z., and Bülow H.E. (2013) Skin-derived cues control arborization of sensory dendrites in Caenorhabditis elegans. Cell, 155(2): 308–320, published online on October 10 as https://doi.org/10.1371/journal.pgen.1004657.

Tecle E., Diaz-Balzac C.A., and Bülow H.E. (2013) Distinct 3-O-sulfated heparan sulfate modification patterns are required for kal-1 dependent neurite branching in a context-dependent manner in Caenorhabditis elegans. G3 (Bethesda), 3(3):541-52. https://doi.org/10.1534/g3.112.005199.

Attreed M., Desbois M., van Kuppevelt T.H., and Bülow, H.E. (2012) Direct visualization of specifically modified extracellular glycans in living animals. Nat. Methods, 9(5):477-479, published online April 1, 2012 as https://doi.org/10.1038/nmeth.1945.

Tornberg J., Sykiotis G.P., Keefe K., Plummer L., Hoang X, Hall J.E., Quinton R., Seminara S.B., Hughes V., Van Vliet G., Van Uum S., Crowley, Jr W.F., Habuchi H., Kimata K., Pitteloud N.*, Bülow, H.E.* (2011) Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci USA, 108(28):11524-11529, published online June 23, 2011 as https://doi.org/10.1073/pnas.1102284108. * contributed equally.

Townley R.A., and Bülow, H.E. (2011) Genetic Analysis of the Heparan modification network in Caenorhabditis elegans. J. Biol. Chem., 286:16824-16831, published March 24, 2011 as https://doi.org/10.1074/jbc.M111.227926.

Aguirre-Chen C., Bülow, H.E., and Kaprelian Z. (2011), C. elegans bicd-1, Homolog of the Drosophila Dynein Accessory Factor, Bicaudal D, Regulates the Branching of PVD Multidendritic Nociceptors. Development, 138:507-518. Published online as https://doi.org/10.1242/dev.060939.

Bhattacharya R., Townley, R.A., Berry K.L., and Bülow, H.E. (2009) The PAPS transporter pst-1/let-462 is required for heparan sulfation and is essential for viability and neural development. J Cell Science, 122:4492-4504. Published online on November 17, 2009 as https://doi.org/10.1242/jcs.050732.