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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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