Developmental Neurobiology Research Interests

Proteoglycans are comprised of a core protein decorated by one or more glycosaminoglycan (GAG) chains.  GAG chains are attached to the serine of a core protein through a linkage region of Xyl-Gly-Gly.  The remainder of the GAG chain is comprised of an alternating series of GlcA-GalNAc sugars.  Some of the GlcA residues are epimerized to IdoA, while either of the two sugars in a disaccharide pair can be sulfate on any of several positions.  The length of the GAG chain and the position of sulfation are not template-driven, leading to an enormous number of possible permutations.  Our research has demonstrated that the GAG chains are essential for signaling guidance cues to neurons: elimination of GAG chains or preventing their synthesis reduces the biological activity of chondroitin sulfate proteoglycans.  Moreover, our recent research has shown that CSPG signaling is dependent on 4-sulfation of GalNAc, especially at the non-reducing end (the furthest from the protein core).  Reducing terminal 4-sulfation with the enzyme arylsulfatase B can significantly alter the actions of CSPGs.  Future research is directed at appyling this discovery to promote recovery of function after spinal cord or brain injury.   

• Pearson, C. S., Mencio, C. P., Barber, A. C., Martin, K. R. and Geller, H. M. Identification of a critical sulfation in chondroitin that inhibits axonal regeneration, eLife, 7:e37139, 2018. [abstract]

• Yu, P., Pearson, C. S., Geller, H. M. Flexible roles for proteoglycan sulfation and receptor signaling, Trends Neurosci.,  41:47-61, 2018. [abstract]

• Janecke, A. R., Li, B., Boehm, M., Krabichler, B., Rohrbach, M., Müller, T., Fuchs, I., Golas, G., Katagiri, Y. Ziegler, S. G., Gahl, W. A., Wilnai, Y., Zoppi, N., Geller, H. M., Giunta, C., Slavotinek, A., Steinmann, B. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations, Am. J. Med. Genetics Part A, 2015. [abstract]

• Susarla, B. T. S., Laing, E. D., Yu, P., Katagiri, Y., Geller, H. M. and Symes, A. J. SMAD proteins differentially regulate TGF-β mediated induction of chondroitin sulfate proteoglycans, J. Neurochem., 119:868-78, 2011.  [abstract]

• Wang, H., Katagiri, Y., McCann, T. E., Unsworth, E., Goldsmith, P., Yu, Z.-Y., Tan, F., Mills, E. M., Wang, Y., Symes, A. J. and Geller, H. M. 4-sulfation of chondroitin is critical for inhibition of axonal growth, J. Cell Sci., 121:3083-3091, 2008. [abstract]

• Laabs, T., Wang, H., McCann, T. E., Katagiri, Y., Fawcett, J. W . and Geller, H. M. Inhibiting GAG chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans, J. Neurosci., 27:14494-14501, 2007.  [abstract]

• Powell, E. M., Fawcett, J. W. and Geller, H. M. Neurite guidance by astrocyte proteoglycans, Mol. Cell. Neurosci., 10:27-42, 1997. [abstract]

When growth cones of neurons encounter CSPGs, they stop or alter their direction of movement.  Our major hypothesis is that CSPGs interact with receptors to initiate an intracellular signaling cascade resulting in an alteration of cytoskeletal dynamics.  Both chondroitin sulfate and heparan sulfate interact with two families of receptors: the LAR family, which includes Receptor Protein Tyrosine Phosphatase RPTP) σ RPTP-δ and the Leukocyte Common Antigen Receptor (LAR), and two members of the Nogo Receptor familiy, NgR1 and NgR3.  This leads to the question of how HS promotes growth and CS inhibits growth. We have establihed that all of these interactions depend upon sulfation: HS and highly sulfated CS bind with high affinity to all five of these receptors.  Another major issue is how binding results in alterations of signaling. We have identified diifferences in the interaction of the LAR family members with proteoglycans which may explain their differential actions on neurons.  Current research is directed at understanding the structural features of these receptors that mediate their interactions with proteoglycan GAG chains.  An additional issue is that there is no binding of these receptors to GAG chains in normal brain, suggesting that there are other ligands involved in normal brain function.  We are in the process of identifying these ligands. 

• Katagiri, Y., Morgan, A. A., Yu, P., Bangayan, N. J., Junka, R., Geller, H. M., Identification of novel binding sites for heparin in RPTPσ: Implications for proteoglycan signaling, J. Biol. Chem., 293:11639-11647, 2018.

• Yi, J. H., Katagiri, Y., Yu, P., Lourie, J., Bangayan, N. J., Symes, A. J. and Geller, H. M. Receptor protein tyrosine phosphatase σ binds to neurons in the adult mouse brain, Exptl. Neurol., 255:12-18, 2014.

• Dickendesher, T. L., Baldwin, K. T., Mironova, Y. A., Koriyama, Y., Raiker, S. J., Askew, K. L., Geoffroy, C. G., Zheng, B., Liepmann, C. D., Katagiri, Y., Benowitz, L. I., Geller, H. M., Giger, R. J. NgR1 and NgR3 are inhibitory receptors for chondroitin sulfate proteoglycans, Nature Neurosci., 15:703-12, 2012.

When growth cones of neurons encounter CSPGs, they stop or alter their direction of movement.  Our major hypothesis is that CSPGs interact with receptors to initiate an intracellular signaling cascade resulting in an alteration of cytoskeletal dynamics.  The major cytoskeletal proteins in growth cones are actin, myosin and tubulin.  Our research has demonstrated alterations in the rate of tubulin polymerization as neurites encounter CSPGs.  We later found that inhibition of myosin II function with blebbistatin can increase axonal growth on CSPG substrates.  While these targeted approaches determined the involvement of these known proteins, a more global approach to identify proteins whose phosphorylation was changed in response to CSPG application resulted in the identificaiton of many different classes of proteins, not only cytoskeletal, involved in the response to CSPGs.  The protein whose phosphorylation was most altered was Lipid Protein Phosphatase Related protein-1, also known as Plasticity Related Gene-3.  Further proteomic experiments determined that LPPR1 interacts with other members of the LPPR family to mediate their biological actions.  Our current research is to investigate the biology and mechanism of action of the LPPR proteins using cell biological and transgenic approaches.

• Yu, P., Agbaegbu, C., Malide, D., Wu, X., Katagiri, Y., Hammer, J. A. and Geller, H. M. Cooperative interactions of LPPR/PRG family members in membrane localization and alteration of cellular morphology, J. Cell Sci., pii: jcs.169789, 2015.

• Yu, P., Pisitkun, T., Wang, G., Wang, R., Katagiri, Y., Gucek, M., Knepper, M. A. and Geller, H. M. Global analysis of neuronal phosphoproteome regulation by chondroitin sulfate proteoglycans, PLoS One, 8:e59285, 2013.

• Yu, P., Santiago, L. Y., Wang, H., Katagiri, Y. and Geller, H. M. Myosin II activity regulates neurite outgrowth and guidance in response to chondroitin sulfate proteoglycans., J. Neurochem., 120:1117-1128, 2012.

• Kelly, T.-A. N., Katagiri, Y., Kumar, P., Chen, I.-I., Vartanian, K. B., Rosoff, W. J., Urbach, J. S. and Geller, H. M. Localized alteration of microtubule polymerization in growth cones at inhibitory boundaries, J. Neurosci. Res., 88:3024-33, 2010.

Astrocytes are the major cell type of the brain, whose numbers far surpass that of neurons.  In the uninjured brain, astrocytes surround neurons and provide nourishment. After injury, astrocytes become hypertrophic and change their physiology to become a major part of the glial scar that inhibits regeneration.  This inhibition is primarily mediated by an increased secretion of extracellular matrix ECM) molecules, especially chondroitin sulfate proteoglycans.  Our research is focused on understanding the regulatory mechanisms that result in this secretion and in changing the composition of the ECM, as well as identifying methods to reduce it and promote regeneration and recovery of function. 

• Pearson, C. S., Solano, A. G., Tilve, S., Mencio, C. P., Martin, K. R. and Geller, H. M. Spatiotemporal distribution of chondroitin sulfate proteoglycans after optic nerve injury in rodents, Exptl. Eye Res., in press.

• Jin, J., Tilve, S., Huang, Z., Geller, H. M., Yu, P. The effect of CSPGs on neuronal cell adhesion, spreading and neurite growth in culture, Neural Regen. Res., 13:289-297, 2018.

• George, N. and Geller, H. M. Extracellular matrix and traumatic brain injury, J. Neurosci. Res., 96:573-588, 2018.

 • Yi, M., Wei, T., Wang, Y., Liu, Q.,  Yu, P., Lu, Q., Chen, G., Gao, X., Geller, H. M., Chen, H. and Yu, Z.  The potassium channel KCa3.1 constitutes a pharmacological target for astrogliosis associated with ischemia stroke,  J. Neuroinflamm., 14:203, 2017

• Yi, M., Yu, P., Lu, Q., Geller, H. M. Yu, Z., and Chen, H. KCa3.1 constitutes a pharmacological target for astrogliosis associated with Alzheimer's Disease, Mol. Cell. Neurosci., S1044-7431, 2016

• Susarla, B., Villapol, S., Yi, J. H., Geller, H. M., Symes, A. J. Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice, ASN Neuro, 6:159-70 2014.

• Yu, Z.-H., Yu, P., Chen, H.-Z., Geller, H. M. Targeted inhibition of KCa3.1 attenuates TGF-β-induced reactive astrogliosis through the Smad2/3 signaling pathway, J. Neurochem., 130:41-9, 2014

• Yi, J. H., Katagiri, Y., Susarla, B., Figge, D., Symes, A. J. and Geller, H. M. Detection of sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice, J. Comp. Neurol., 520:3295-313, 2012.

• Yu, P., Wang, H., Katagiri, Y. and Geller, H. M. An in vitro model of reactive astrogliosis and its effect on neuronal growth. In: Astrocytes, Methods and Protocols, R. Milner, ed., Humana Press, Methods in Molecular Biology, 814:327-40, 2012

• Susarla, B. T. S., Laing, E. D., Yu, P., Katagiri, Y., Geller, H. M. and Symes, A. J. SMAD proteins differentially regulate TGF-β mediated induction of chondroitin sulfate proteoglycans, J. Neurochem., 119:868-78, 2011.

• Laabs, T., Wang, H., McCann, T. E., Katagiri, Y., Fawcett, J. W . and Geller, H. M. Inhibiting GAG chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans, J. Neurosci., 27:14494-14501, 2007.

• Powell, E. M., Calle-Patino, Y. A., Mercado, M. L. T. and Geller, H. M. Protein kinase C mediates neurite guidance at an astrocyte boundary, Glia, 33:288-297, 2001.

Studies of axonal growth and guidance cues have primarily focused on soluble and substrate-bound molecules. However, axons are growing in a physical as well as a chemical environment.  In addition, growth cones exert physical forces on their substrates. This part of our research, in collaboration with Dr. Jeffrey Urbach of Georgetown University, is directed as understanding the role of physical forces in the regulation of axonal growth. Thus, different neuronal populations react differently to the stiffness of their substrate. We are also investigating the forces generated by growing axons using a combination of traction force and total internal reflection (TIRF) microscopy. 

• Polackwich, J., Koch, D., McAllister, R., Urbach, J. S. , Geller, H. M. Traction force and tension fluctuations in growing axons, Frontiers In Cellular Neuroscience, 2015 doi:10.3389/fncel.2015.00417

• Koch, D., Rosoff, W. J., Jian, J., Geller, H. M. and Urbach, J. S. Strength in the periphery: Growth cone biomechanics and substrate rigidity response in peripheral and central nervous system neurons, Biophys. J., 102:452-460, 2012.

• Kelly, T.-A. N., Katagiri, Y., Kumar, P., Chen, I.-I., Vartanian, K. B., Rosoff, W. J., Urbach, J. S. and Geller, H. M. Localized alteration of microtubule polymerization in growth cones at inhibitory boundaries, J. Neurosci. Res., 88:3024-33, 2010.

The glial scar is a major impediment to regrowing axons.  Our goal is to develop tissue engineering methods to encourage neurons to grow through the scar.  These methods include understanding how neurons grow in confinement as well as developing substrates that promote axonal growth.  Further research will use new methods of substrate fabrication as well as new biomatierials. 

• Smirnov, M. S., Cabral, K. A., Geller, H. M. and Urbach, J. S. The effects of confinement on neuronal growth cone morphology and velocity, Biomaterials, 35:6750-7, 2014.

• Mora, K. E., Cohen, J. D., Yu, P., Geller, H. M. and Morgan, N. Y., Microfluidic deposition of chondroitin sulfate proteoglycan surface gradients for neural cell culture. Microsystems for Measurement and Instrumentation (MAMNA), 20-23, 2013.

• Zhou, Z., Yu, P., Geller, H. M. and Ober, C. Biomimetic polymer brushes containing tethered acetylcholine analogs for protein and hippocampal neuronal cell patterning, Biomacromolecules, 14:529-37, 2013.

• Zhou, Z., Yu, P., Geller, H. M. and Ober, C. The role of hydrogels with tethered acetylcholine functionality on the adhesion and viability of hippocampus neurons and glial cells. Biomaterials, 33:2473-2481, 2012.

• Krsko, P., McCann, T. E., Thach, T.-T., Laabs, T.L., Geller, H. M. and Libera, M. Length-scale mediated adhesion and directed growth of neural cells by surface-patterned poly(ethylene glycol) hydrogels, Biomaterials, 30:721-729, 2009.

• Geller, H. M. and Fawcett, J. W. Building a bridge: Engineering spinal cord repair, Exptl. Neurol, 174:125-36, 2002.