Associate Professor, Department of Genetics
Associate Professor, Dominick P. Purpura Department of Neuroscience
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 navigate the extracellular space in order to connect to their appropriate partners. 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 HS determine the path of developing axons.
We have previously shown that distinct modification patterns in HS (a polysaccharide) serve specific functions during nervous system 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 shaping 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.
In a related project we are investigating a pathological dimension of HS by studying Kallmann Syndrome, a human genetic disease with specific neurological defects. Using C. elegans as a model, we have shown that kal-1, the nematode orthologue of the gene mutated in human Kallmann patients, has a role in axon branching and requires HS with specific modifications for these functions. Our goal here is to understand how KAL-1 functions on a molecular level during disease and development. We approach this by conducting genetic screens to identify novel genes that interact with kal-1.
In summary, our studies are directed towards a better understanding of how heparan sulfate and its modifications (the ‘HS code’) functions during 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. Ann. 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.
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