Genetics of Nervous System Development
My lab uses the small nematode C. elegans with its simple and well characterized nervous system as a genetic model. We are trying to understand how growing axons and dendrites navigate the extracellular space to connect to their partners and be appropriately patterned.
The extracellular space is filled with a complex mixture of proteins and proteoglycans e.g. heparan sulfate (HS) proteoglycans which are a particular focus of the lab. 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 helps shape the nervous system. Our goal is to decipher the information contained in HS, determine the factors that create and modulate it and describe the genes that respond to it. We are also investigating a pathological dimension of HS by studying Kallmann Syndrome, a human genetic disease with specific neurological defects in which we have identified mutations in HS genes.
In another project we are studying the development of dendrites in polymodal multidendritic neurons of C. elegans. We are aiming to understand how the complex dendritic arbors that resemble menorah-like candelabras are patterned. In summary, we are using genetic approaches coupled with biochemical and advanced imaging approaches to understand the function of genes involved in development and disease of the nervous system.
Bülow, H.E., and Hobert, O. (2004) Differential sulfations and epimerization define heparan sulfate specificity in nervous system development. Neuron, 41:723-736.
Bülow, H.E., Boulin, T., and Hobert, O. (2004) Differential functions of the C. elegans FGF receptor in axon outgrowth and maintenance of axon position. Neuron, 42:367-374.
Bülow, H.E.*, and Hobert, O.* (2006) The Molecular Diversity of Glycosaminoglycans shapes Animal Development. Annu. Rev. Cell. Dev. Biol., 22:375-407. * corresponding authors
Bülow, H.E.*, Tjoe, N., Townley, R.A., Didiano, D., van Kuppevelt, T.H., and Hobert, O. (2008) Extracellular sugar modifications provide instructive and cell-specific information for axon guidance choices. Current Biology, 18:1978-1985, * corresponding author. Faculty of 1000 Biology Evaluation: F1000 Factor 10 (must read) (Jan. 2009).
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.
MacColl G.S., Quinton R., Bülow, H.E. (2010), Biology of KAL1 and its orthologs: implications for X-linked Kallmann's syndrome and the search for novel candidate genes. Frontiers of Hormone Research, 39:62-77.
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.
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 doi:10.1074/jbc.M111.227926.
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 doi:10.1073/pnas.1102284108, * contributed equally.
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 doi:10.1038/nmeth.1945.
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. PMCID: PMC3583460.
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 http://dx.doi.org/10.1016/j.cell.2013.08.058.
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. doi: 10.1534/g3.114.012591. [Epub ahead of print].
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 Genet., published online on September 18;10(9):e1004657. doi: 10.1371/journal.pgen.1004657.
Dong X, Shen K*, and Bülow H.E.* (2015) Intrinsic and extrinsic mechanisms of dendrite morphogenesis. Annu. Rev. Physiol., 77:18.1–18.30. * corresponding authors
Attreed M., and Bülow H.E. (2015) A Transgenic Approach to Live Imaging of Heparan Sulfate Modification patterns. Methods in Molecular Biology, 1229:253-68. doi: 10.1007/978-1-4939-1714-3_22.
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, published online on April 27, 2015 as doi: 10.1534/genetics.115.177006.
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.
Attreed, M., Saied-Santiago, K., and Bülow H.E. (2016) Conservation of anatomically restricted glycosaminoglycan structures in divergent nematode species. Glycobiology, published online on March 13 as doi: 10.1093/glycob/cww037.
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