Tiny worm could lead to nerve injury treatments
Published on: 8 January 2015
About
The Hilliard laboratory is focused on understanding the molecular mechanisms that regulate neuronal development, maintenance and repair, using C. elegans as a model system. The group’s current research goals are: (1) how the axon, which is the longest of the neuronal processes, is subdivided into structurally and functionally different compartments, (2) how the axon maintains its structure and function over the lifetime of the organism, and (3) how the axon can be repaired when severing damage occurs.
Using a combination of molecular biology, genetics, laser manipulations, and imaging approaches, the Hilliard group has made a number of key discoveries in these research areas. They include: the axonal protective function of a conserved alpha tubulin acetyltransferase (Cell Reports, 2014); the role of conserved apoptotic molecules in axonal degeneration; and the identification of the molecular mechanisms that regulate axonal fusion, an axonal repair event in which the two separated fragments of an injured axon rejoin and reconstitute the original tract (Nature, 2015). This latest discovery on how axonal fusion is achieved has important implications for medical practice: a similar strategy may be used to facilitate nerve repair.
The Hilliard group has been successful in attracting competitive funding that includes an ARC Discovery Project, an NHMRC Senior Research Fellowship, and a NHMRC-ARC Dementia Fellowship.
Podcast
Research Areas
- Axonal degeneration
- Axonal regeneration
- Neuronal development
Giordano-Santini, Rosina, Kaulich, Eva, Galbraith, Kate M., Ritchie, Fiona K., Wang, Wei, Li, Zhaoyu and Hilliard, Massimo A. (2020). Fusogen-mediated neuron−neuron fusion disrupts neural circuit connectivity and alters animal behavior. Proceedings of the National Academy of Sciences, 117 (37), 201919063-23065. doi: 10.1073/pnas.1919063117
Coakley, Sean, Ritchie, Fiona K., Galbraith, Kate M. and Hilliard, Massimo A. (2020) Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration. Nature Communications, 11 1: 1-12. doi:10.1038/s41467-019-13795-x
Axonal repair by fusion: pitfalls, consequences and solutions
Neumann, Brent and Hilliard, Massimo A. (2019) Axonal repair by fusion: pitfalls, consequences and solutions. FASEB Journal, 33 12: 13071-13074. doi:10.1096/fj.201901407R
Linton, Casey, Riyadh, M. Asrafuzzaman, Ho, Xue Yan, Neumann, Brent, Giordano-Santini, Rosina and Hilliard, Massimo A. (2019) Disruption of RAB-5 increases EFF-1 fusogen availability at the cell surface and promotes the regenerative axonal fusion capacity of the neuron. Journal of Neuroscience, 39 15: 2823-2836. doi:10.1523/jneurosci.1952-18.2019
Axonal fusion: an alternative and efficient mechanism of nerve repair
Neumann, Brent, Linton, Casey, Giordano-Santini, Rosina and Hilliard, Massimo A. (2019) Axonal fusion: an alternative and efficient mechanism of nerve repair. Progress in Neurobiology, 173 88-101. doi:10.1016/j.pneurobio.2018.11.004
Neuronal sub-compartmentalization: a strategy to optimize neuronal function
Donato, Alessandra, Kagias, Konstantinos, Zhang, Yun and Hilliard, Massimo A. (2019) Neuronal sub-compartmentalization: a strategy to optimize neuronal function. Biological Reviews, . doi:10.1111/brv.12487
Offenburger, Sarah-Lena, Ho, Xue Yan, Tachie-Menson, Theresa, Coakley, Sean, Hilliard, Massimo A. and Gartner, Anton (2018) 6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33. PLoS Genetics, 14 1: 1-27. doi:10.1371/journal.pgen.1007125
Chand, Kirat K., Lee, Kah Meng, Lee, John D., Qiu, Hao, Willis, Emily F., Lavidis, Nickolas A., Hilliard, Massimo A. and Noakes, Peter G. (2018) Defects in synaptic transmission at the neuromuscular junction precedes motor deficits in a TDP-43Q331K transgenic mouse model of amyotrophic lateral sclerosis. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 32 5: fj201700835R-2689. doi:10.1096/fj.201700835R
The heterochronic gene lin-14 controls axonal degeneration in C. elegans neurons
Ritchie, Fiona K., Knable, Rhianna, Chaplin, Justin, Gursanscky, Rhiannon, Gallegos, Maria, Neumann, Brent and Hilliard, Massimo A. (2017) The heterochronic gene lin-14 controls axonal degeneration in C. elegans neurons. Cell Reports, 20 12: 2955-2965. doi:10.1016/j.celrep.2017.08.083
Gokce, Sertan Kutal, Hegarty, Evan Marley, Mondal, Sudip, Zhao, Peisen, Ghorashian, Navid, Hilliard, Massimo A. and Ben-Yakar, Adela (2017) A multi-trap microfluidic chip enabling longitudinal studies of nerve regeneration in Caenorhabditis elegans. Scientific Reports, 7 9837: 9837. doi:10.1038/s41598-017-10302-4
Abay, Zehra C, Wong, Michelle Yu-Ying, Teoh, Jean-Sébastien, Vijayaraghavan, Tarika, Hilliard, Massimo A and Neumann, Brent (2017) Phosphatidylserine save-me signals drive functional recovery of severed axons in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America, 114 47: 1-10. doi:10.1073/pnas.1703807114
Fogarty, Matthew J., Klenowski, Paul M., Lee, John D., Drieberg-Thompson, Joy R., Bartlett, Selena E., Ngo, Shyuan T., Hilliard, Massimo A., Bellingham, Mark C. and Noakes, Peter G. (2016) Cortical synaptic and dendritic spine abnormalities in a presymptomatic TDP-43 model of amyotrophic lateral sclerosis. Scientific Reports, 6 . doi:10.1038/srep37968
Cell-cell fusion in the nervous system: alternative mechanisms of development, injury and repair
Giordano-Santini, Rosina, Linton, Casey and Hilliard, Massimo A. (2016) Cell-cell fusion in the nervous system: alternative mechanisms of development, injury and repair. Seminars in Cell and Developmental Biology, 60 146-154. doi:10.1016/j.semcdb.2016.06.019
Gallotta, Ivan, Mazzarella, Nadia, Donato, Alessandra, Esposito, Alessandro, Chaplin, Justin C., Castro, Silvana, Zampi, Giuseppina, Battaglia, Giorgio S., Hilliard, Massimo A., Bazzicalupo, Paolo and Di Schiavi, Elia (2016) Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism. Human Molecular Genetics, . doi:10.1093/hmg/ddw119
The apoptotic engulfment machinery regulates axonal degeneration in C. elegans neurons
Nichols, Annika L.A., Meelkop, Ellen, Linton, Casey, Giordano-Santini, Rosina, Sullivan, Robert K., Donato, Alessandra, Nolan, Cara, Hall, David H., Xue, Ding, Neumann, Brent and Hilliard, Massimo A. (2016) The apoptotic engulfment machinery regulates axonal degeneration in C. elegans neurons. Cell Reports, 14 7: 1673-1683. doi:10.1016/j.celrep.2016.01.050
EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway
Neumann, Brent, Coakley, Sean, Giordano-Santini, Rosina, Linton, Casey, Lee, Eui Seung, Nakagawa, Akihisa, Xue, Ding and Hilliard, Massimo A. (2015) EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature, 517 7533: 219-222. doi:10.1038/nature14102
Lee, Hyewon, Kim, Shin Ae, Coakley, Sean, Mugno, Paula, Hammarlund, Marc, Hilliard, Massimo A. and Lu, Hang (2014) A multi-channel device for high-density target-selective stimulation and long-term monitoring of cells and subcellular features in C. elegans. Lab on a Chip - Miniaturisation for Chemistry and Biology, 14 23: 4513-4522. doi:10.1039/c4lc00789a
Loss of MEC-17 leads to microtubule instability and axonal degeneration
Neumann, Brent and Hilliard, Massimo A. (2014) Loss of MEC-17 leads to microtubule instability and axonal degeneration. Cell Reports, 6 1: 93-103. doi:10.1016/j.celrep.2013.12.004
Williams, Daniel C., El Bejjani, Rachid, Mugno Ramirez, Paula, Coakley, Sean, Kim, Shin Ae, Lee, Hyewon, Wen, Quan, Samuel, Aravi, Lu, Hang, Hilliard, Massimo A. and Hammarlund, Marc (2013) Rapid and permanent neuronal inactivation in vivo via subcellular generation of reactive oxygen with the use of KillerRed. Cell Reports, 5 2: 553-563. doi:10.1016/j.celrep.2013.09.023
Kirszenblat, Leonie, Neumann, Brent, Coakley, Sean and Massimo Hilliard (2013) A dominant mutation in mec-7/β-tubulin affects axon development and regeneration in Caenorhabditis elegans neurons. Molecular Biology of the Cell,24 3: 285-296. doi:10.1091/mbc.E12-06-0441
A core metabolic enzyme mediates resistance to phosphine gas
Schlipalius, David I., Valmas, Nicholas, Tuck, Andrew G., Jagadeesan, Rajeswaran, Ma, Li, Kaur, Ramandeep, Goldinger, Anita, Anderson, Cameron, Kuang, Jujiao, Zuryn, Steven, Mau, Yosep S., Cheng, Qiang, Collins, Patrick J., Nayak, Manoj K., Schirra, Horst Joachim, Hilliard, Massimo A. and Ebert, Paul R. (2012) A core metabolic enzyme mediates resistance to phosphine gas. Science, 338 6108: 807-810. doi:10.1126/science.1224951
Cáceres, Ivan de Carlos, Valmas, Nicholas, Hilliard, Massimo A. and Lu, Hang (2012) Laterally orienting C. elegans using geometry at microscale for high-throughput visual screens in neurodegeneration and neuronal development studies. PLoS One, 7 4: e35037.1-e35037.8. doi:10.1371/journal.pone.0035037
LIN-44/Wnt directs dendrite outgrowth through LIN-17/Frizzled in C. elegans neurons
Kirszenblat, Leonie, Pattabiraman, Divya and Hilliard, Massimo A. (2011) LIN-44/Wnt directs dendrite outgrowth through LIN-17/Frizzled in C. elegans neurons. PLoS Biology, 9 9: 0nline. doi:10.1371/journal.pbio.1001157
Axonal regeneration proceeds through specific axonal fusion in transected C. elegans neurons
Neumann, Brent, Nguyen, Ken C. Q., Hall, David H., Ben-Yakar, Adela and Hilliard, Massimo A. (2011) Axonal regeneration proceeds through specific axonal fusion in transected C. elegans neurons. Developmental Dynamics,240 6: 1365-1372. doi:10.1002/dvdy.22606
Big ideas for small brains: What can psychiatry learn from worms, flies, bees and fish?
Burne, T. H. J., Scott, E., van Swinderen, B., Hilliard, M., Reinhard, J., Claudianos, C., Eyles, D. W. and McGrath, J. J. (2011) Big ideas for small brains: What can psychiatry learn from worms, flies, bees and fish?. Molecular Psychiatry,16 1: 7-16. doi:10.1038/mp.2010.35
Axonal degeneration and regeneration: a mechanistic tug-of-war
Hilliard, Massimo (2009) Axonal degeneration and regeneration: a mechanistic tug-of-war. Journal Of Neurochemistry, 108 1: 23-32. doi:10.1111/j.1471-4159.2008.05754.x
Femtosecond laser nanoaxotomy lab-on-a-chip for in vivo nerve regeneration studies
Guo, Samuel X., Bourgeois, Frederic, Chokshi, Trushal, Durr, Nicholas J., Hilliard, Massimo A., Chronis, Nikos and Ben-Yakar, Adela (2008) Femtosecond laser nanoaxotomy lab-on-a-chip for in vivo nerve regeneration studies.Nature Methods, 5 6: 531-533. doi:10.1038/nmeth.1203
Chalasani, Sreekanth H., Feinberg, Evan H. and Hilliard, Massimo A. (2007) Global 'worming'. Genome Biology, 8 9: 314-1-314-3. doi:10.1186/gb-2007-8-9-314
Pan, Chun-Liang, Howell, James Endres, Clark, Scott G., Hilliard, Massimo, Cordes, Shaun, Bargmann, Cornelia I. and Garriga, Gian (2006) Multiple Wnts and frizzled receptors regulate anteriorly directed cell and growth cone migrations in Caenorhabditis elegans. Developmental cell, 10 3: 367-377. doi:10.1016/j.devcel.2006.02.010
Wnt signals and Frizzled activity orient anterior-posterior axon outgrowth in C. elegans
Hilliard, Massimo A. and Bargmann, Cornelia I. (2006) Wnt signals and Frizzled activity orient anterior-posterior axon outgrowth in C. elegans. Developmental Cell, 10 3: 379-390. doi:10.1016/j.devcel.2006.01.013
Sapio, Maria Rosaria, Hilliard, Massimo A., Cermola, Michele, Favre, Reneé and Bazzicalupo, Paolo (2005) The Zona Pellucida domain containing proteins, CUT-1, CUT-3 and CUT-5, play essential roles in the development of the larval alae in Caenorhabditis elegans. Developmental Biology, 282 1: 231-245. doi:10.1016/j.ydbio.2005.03.011
In vivo imaging of C. elegans ASH neurons: Cellular response and adaptation to chemical repellents
Hilliard, Massimo A., Apicella, Alfonso J., Kerr, Rex, Suzuki, Hiroshi, Bazzicalupo, Paolo and Schafer, William R. (2005) In vivo imaging of C. elegans ASH neurons: Cellular response and adaptation to chemical repellents. The EMBO Journal 24, 1489-1489, 24 63-72. doi:10.1038/sj.emboj.7600493
Hilliard, Massimo A., Bergamasco, Carmela, Arbucci, Salvatore, Plasterk, Ronald H. A. and Bazzicalupo, Paolo (2004) Worms taste bitter: ASH neurons, QUI-1, GPA-3 and ODR-3 mediate quinine avoidance in Caenorhabditis elegans.The EMBO Journal, 23 5: 1101-1111. doi:10.1038/sj.emboj.7600107
C. elegans responds to chemical repellents by integrating sensory inputs from the head and the tail
Hilliard, Massimo A., Bargmann, Cornelia I. and Bazzicalupo, Paolo (2002) C. elegans responds to chemical repellents by integrating sensory inputs from the head and the tail. Current Biology, 12 9: 730-734. doi:10.1016/S0960-9822(02)00813-8
Axonal degeneration
How neurons can maintain their axonal structure and function over time is not well understood. Axonal degeneration is a critical and common feature of many peripheral neuropathies, neurodegenerative diseases and nerve injuries. The genetic factors and the cellular mechanisms that prevent axonal degeneration under normal conditions and that trigger it under pathological ones are still largely unknown. We aim to use C. elegans genetics to identify the molecules and the mechanisms that control these processes.
Axonal regeneration
How some axons can regenerate after nerve damage while others cannot is a crucial question in neurobiology, and the answers will be of great value for the medical handling of neurodegenerative diseases and of traumatic nerve injuries. Largely unknown are the molecules and the mechanisms underlying this important biological process. In C. elegans, a new laser-based technology allows single neuron axotomy in living animals, and axonal regeneration can now be visualised in real-time and tackled with a genetic approach. Our goal is to identify the genes and conditions that control this fascinating process.
Neuronal polarity and axonal guidance
Neurons are highly polarized cells with distinct domains such as axons and dendrites. The polarity of a developing neuron determines the precise exit point of its axon as well as the initial trajectory of axon outgrowth. Understanding how neurons establish and orient polarity with respect to extracellular cues is an important and challenging problem in neurobiology. We wish to understand how different secreted cues regulate the orientation of neuronal polarity and axonal/dendrite guidance in vivo.
- Associate Professor Hang Lu - Georgia Institute of Technology, Atlanta, USA
- Associate Professor Yun Zhang - Harvard University, Cambridge, USA
- Professor Ding Xue - University of Colorado, Boulder, USA.
- Prof. Fred Meunier - QBI, The University of Queensland, Brisbane, Australia
- A/Prof Peter Noakes - SMBS, The University of Queensland, Brisbane, Australia
- Dr Paolo Bazzicalupo and Dr Elia Di Schiavi - Institute of Genetics and Biophysics, Naples, Italy
- Professor Paul Ebert - The University of Queensland, Brisbane, Australia