Piper Lab - Neural stem cells in development and disease

Research directions

We use the cortex, cerebellum and spinal cord of the developing and adult mouse as model systems to elucidate the biology of neural stem cells within the brain. Ultimately, we hope to define the genes that drive the differentiation of neural progenitor cells into either neurons or glia, work that will provide insights into neurodevelopmental disorders, ageing and cancer. Dr. Piper currently has funding from the  ARC (Discovery Project grant; 2016-2018) to investigate how neural stem cell quiescence in the adult brain is co-ordinated. This work will provide pivotal insights into how ongoing neurogenesis in the adult brain is regulated, and the behavioural consequences of deficits to this process. Dr. Piper is funded also by the Cancer Council Queensland (2016-2017) to investigate the transcriptional regulation of stem cell biology within the developing cerebellum and in medulloblastoma, a cerebellar tumour that is the most common malignant paediatric brain cancer. We envisage that this research will provide important insights into the control of neural stem cell differentiation within the cerebellum, as well as providing avenues that will lead to improved treatment for this devastating disorder.

Current collaborations

  • Professor Linda Richards - Queensland Brain Institute, The University of Queensland
  • Assoc. Prof. Thomas Burne - Queensland Brain Institute, The University of Queensland
  • Professor Richard Gronostajski - Department of Biochemistry, State University of New York at Buffalo
  • Professor Francois Guillemot - Division of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London, UK
  • Assoc Prof. Mikael Boden - School of Chemistry and Molecular Biosciences
  • Dr Aaron Smith, QUT

Contact

Dr Michael Piper
NHMRC Research Fellow
Queensland Brain Institute and the School of Biomedical Sciences
The University of Queensland
Brisbane Qld 4072
Tel: (+61 7) 3365 4484
Email: m.piper@uq.edu.au

Opportunities for new researchers

Our lab uses a variety of techniques to probe neural stem cell biology, including molecular biology, immunocytochemistry, magnetic resonance imaging and behavioural approaches.  We also use a range of high end imaging modalities.  Our lab comes from diverse backgrounds, and we are always looking for people with complementary techniques, such as electrophysiology or bioinformatics, to join our group.

Positions are available across our research program for undergraduates, honours students, PhD students, and postdocs, and we are happy to entertain new ideas.  If you are interested in joining the lab, please contact Mike.

Transcriptional regulation of cortical development

We are interested in understanding how neural stem cell proliferation and differentiation is regulated at a transcriptional level within the developing cerebral cortex. Using the developing mouse brain as a model system, we are using a suite of molecular and cellular techniques to understand how the cerebral cortex, which is one of the most complex regions of the nervous system, develops embryonically. One of our major focuses in on the transcription factor NFIX, and how it promotes neural stem cell differentiation.  This work will provide insights into human neurodevelopmental disorders that arise as a result of abnormal neural stem cell biology in utero.

Development of the cerebral cortex
Development of the cerebral cortex

The cerebral cortex is a critical part of the brain.  Here, a coronal section of the developing mouse cerebral cortex is shown.  There are two main progenitor cell types in the developing cortex, the radial glia (shown in red) and intermediate progenitor cells (shown in green). Defects in the proliferation and differentiation of these cells can give rise to cortical deficits such as microcephaly (smaller brain) or macrocephaly (larger brain). Image courtesy of Lachlan Harris.

Adult neurogenesis

The birth of new neurons within the cerebral cortex, a process termed neurogenesis, plays a critical role in learning, memory and spatial navigation. We are investigating various aspects of adult neurogenesis in rodent models, including neural stem cell quiescence and dendrite elongation and spine formation. We are also interrogating the consequences of abnormal neurogenesis using behavioural tests for learning and memory.

We employ a range of transgenic mice to investigate adult neurogenesis, coupled with techniques ranging from immunocytochemistry, behavioural testing, analysis of axonal connectivity and genome-wide sequencing platforms.  Given the critical roles that learning and memory play in our everyday lives, and the fact that neurogenesis within the adult brain diminishes with age, this research will provide fundamental insights into how this vital process is co-ordinated at a cellular and molecular level. This work is supported by the Australian Research Council.

Adult neural stem cells
Adult neural stem cells

Neural stem cells are found within the dentate gyrus of the adult mammalian brain. Here, a neural stem cell in the dentate gyrus of the adult mouse brain has been identified by the expression of GFAP (green), a marker protein expressed by these cells. Cell nuclei are labelled in white. Image courtesy of Lachlan Harris.

Immature neurons
Immature neurons

Newly born neurons within the adult dentate gyrus extend processes and become integrated into the existing hippocampal circuitry.  In this image, newly born, immature neurons are identified through the expression of DCX (in green) within the adult mouse dentate gyrus. The new neurons can be seen extending processes into the granule cell layer of the dentate gyrus (cell nuclei can be seen in white). Image courtesy of Lachlan Harris.

Hippocampal neurogenesis
Hippocampal neurogenesis

Neurons born within the adult hippocampus from endogenous neural stem cells play a key role in learning and memory.  Here, a neuron from the adult mouse dentate gyrus (where neurogenesis within the adult hippocampus takes place) is labelled.  The elaborate dendritic tree of the neuron is critical to enable learning and memory to take place. Image courtesy of Sabrina Oishi.

Cerebellar development and medulloblastoma

Neural stem and progenitor cells are also required for the formation of the cerebellum, a hindbrain structure that is pivotal for balance, gait and posture. Indeed, cerebellar granule neurons are the most common neuron found within the nervous system. We are currently investigating the mechanisms that control how granule neuron progenitor cells (GNPs) proliferate and ultimately differentiate within the maturing cerebellum. This work is revealing key pathways that mediate GNP differentiation. Importantly, the very same pathways are often misregulated in medulloblastoma, a cancer of the cerebellum that is the most common paediatric malignancy of the nervous system. As such, our work will deepen our understanding of normal cerebellar development, and will provide a platform to develop new methods to diagnose and treat medulloblastoma. This work is partially funded by Cancer Council Queensland.

The cerebellum
The cerebellum

The cerebellum regulates key functions including balance, gait and motor learning. Within the cerebellum, neural function is regulated by glial cells, such as astrocytes.  Here, a specific population of astrocytes in the adult cerebellum known as Bergmann glia, are shown through the expression of GFAP (green). These glia predominantly express the transcription factor NFIX (red).  Cell nuclei are shown in blue.  Image courtesy of James Fraser.

Purkinje neurons – masters of integration
Purkinje neurons – masters of integration

Within the mature cerebellar cortex, Purkinje neurons play a pivotal role in comparing motor plans with ongoing sensory feedback, to enable real-time corrections to ongoing movements to be enacted. Here, Purkinje neurons within the cerebellar cortex are shown through the expression of calbindin (green). Image courtesy of James Fraser.

Transcription factors and melanoma

More recently, in collaboration with Dr. Aaron Smith (Queensland University of Technology), we have been interrogating how different transcription factors mediate the biology of a skin cancer called melanoma. Melanoma incidence in Australia is high, yet our understanding of the processes by which melanoma cells switch between proliferating and metastasising remain limited. Melanoma cells show a large degree of heterogeneity, with cells expressing transcription factors such as MITF being highly proliferative, whereas cells expressing BRN2 are more invasive. Our work has identified a novel role for a transcription factor called NFIB in promoting tumour invasiveness and metastasis. We anticipate that this work will lead to better tools to treat this devastating disorder.

Cultured melanoma cells
Cultured melanoma cells

Melanoma cells show a large degree of heterogeneity. Here, melanoma cells are grown as spheres in an in vitro culture system. We have used immunocytochemistry to reveal the expression of BRN2 (red) and MITF (green) in these melanoma-spheres, revealing the differential expression of these factors within the cellular population. Image courtesy of Mitchell Fane.

Harris L, Zalucki O, Gobius I, McDonald H, Osinski J, Harvey TJ, Essebier A, Vidovic D, Gladwyn-Ng I, Burne TH, Heng JI, Richards LJ, Gronostajski RM, Piper M (2017) Transcriptional regulation of intermediate progenitor cell generation during hippocampal development.  Development, 143; 4620-4630.

Oishi, Sabrina, Zalucki, Oressia, Premarathne, Susitha, Wood, Stephen A. and Piper, Michael (2016) USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus. Neurogenesis3 1: 1-9. doi:10.1080/23262133.2016.1235524

Iyer, Swati, Pennisi, David J. and Piper, Michael (2016) Crim1 – a regulator of developmental organogenesis. Histology And Histopathology31 10: 1049-1057. doi:10.14670/HH-11-766

Stringer, Brett W., Bunt, Jens, Day, Bryan W., Barry, Guy, Jamieson, Paul R., Ensbey, Kathleen S., Bruce, Zara C., Goasdoué, Kate, Vidal, Helene, Charmsaz, Sara, Smith, Fiona M., Cooper, Leanne T., Piper, Michael, Boyd, Andrew W. and Richards, Linda J.(2016) Nuclear factor one B (NFIB) encodes a subtype-specific tumour suppressor in glioblastoma. Oncotarget7 20: 29306-12320. doi:10.18632/oncotarget.8720

Oishi, Sabrina, Premaratne, Susitha, Harvey, Tracey J., Iyer, Swati, Dixon, Chantelle, Alexander, Suzanne, Burne, Thomas H. J., Wood, Stephen A. and Piper, Michael (2016) Usp9x-deficiency disrupts the morphological development of the postnatal hippocampal dentate gyrus. Scientific Reports6 25783.1-25783.13. doi:10.1038/srep25783

Harris, Lachlan, Zalucki, Oressia, Piper, Michael and Heng, Julian Ik-Tsen (2016) Insights into the biology and therapeutic applications of neural stem cells. Stem Cells International2016 . doi:10.1155/2016/9745315

Iyer, Swati, Chou, Fang Yu, Wang, Richard, Chiu, Han Sheng, Raju, Vinay K. Sundar, Little, Melissa H., Thomas, Walter G., Piper, Michael and Pennisi, David J. (2016) Crim1 has cell-autonomous and paracrine roles during embryonic heart development. Scientific Reports6 19832 .1-19832 .15. doi:10.1038/srep19832

Leung L, Harris WA, Holt CE, Piper M (2015) NF-protocadherin regulates retinal ganglion cell axon behaviour in the developing visual system. PLoS One, 10(10): e0141290.

Vidovic D, Harris L, Harvey T, Heng YHE, Smith A, Osinski J, Hughes J, Thomas P, Gronostajski R, Bailey T, Piper M(2015) Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX. Brain Research, 1616, 71-87.

Heng YHE, Zhou B, Harris L, Harvey T, Smith A, Horne E, Martynoga B, Andersen J, Achimastou A, Cato K, Richards L, Gronostajski R, Yeo G, Guillemot F, Bailey T, Piper M (2015) NFIX regulates proliferation and migration within the murine SVZ neurogenic niche. Cerebral Cortex 25:3758-3778.

Piper M, Barry G, Harvey TJ, McLeay R, Smith AG, Harris L, Mason S, Stringer BW, Day BW, Wray NR, Gronostajski RM, Bailey TL, Boyd AW, Richards LJ (2014) NFIB-mediated repression of the epigenetic factor Ezh2 regulates cortical development. The Journal of Neuroscience, 34:2921-2930.

Heng YHE, McLeay R, Harvey TJ, Smith AG, Barry G, Cato K, Plachez C, Little E, Mason S, Dixon C, Gronostajski RM, Bailey TL, Richards LJ, Piper M (2014) NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis. Cerebral Cortex, 24; 261-279.

Martynoga B, Mateo JL, Zhou B, Andersen J, Achimastou A, Urban N, van den Berg D, Georgopoulou D, Hadjur S, Wittbrodt J, Ettwiller L, Piper M, Gronostajski RM and Guillemot F. 2013. Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence. Genes Dev 27(16):1769-1786.

Plachez C, Cato K, McLeay R, Heng YHE, Bailey TL, Gronostajski RM, Richards LJ, Piper M (2012) Expression of Nuclear Factor One A and B in the olfactory bulb. The Journal of Comparative Neurology, 520:3135-3149.

Subramanian L, Sarkar A, Shetty A, Muralidharan B, Padmanabhan H, Piper M, Monuki E, Bach I, Gronostajski RM, Richards LJ, Tole S. (2011) Lhx2 is necessary and sufficient to suppress astrogliogenesis and promotes neurogenesis in the developing hippocampus. Proceedings of the National Academy of Sciences, 108: 265-274.

Zivraj KH, Tung YCL, Piper M, Gumy L, Fawcell J, Yeo GSH, Holt CE. Subcelllular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs. (2010) The Journal of Neuroscience, 30(46):15464-15478.

Piper M, Barry G, Hawkins J, Mason S, Lindwall C, Little E, Sarkar A, Moldrich RX, Boyle GM, Tole S, Gronostajski RM, Bailey T, Richards LJ. NFIA regulates telencephalic progenitor cell differentiation through repression of the Notch effector Hes1. (2010) The Journal of Neuroscience, 30(27):9127-9139.

Piper M, Plachez C, Zalucki O, Fothergill T, Guy Goudreau, Erzurumlu R, Gu C, Richards LJ. (2009) Neuropilin 1-Sema signalling regulates crossing of cingulate pioneering axons during development of the corpus callosum. Cerebral Cortex, 19:i11-i21.

Barry G, Piper M, Lindwall C, Moldrich R, Mason S, Little E, Sarkar A, Tole S, Gronostajski RM, Richards LJ (2008) Specific glial populations regulate hippocampal morphogenesis. The Journal of Neuroscience, 28(47): 12328-12340.

Piper M, Dwidevy A, Leung L, Bradley RS, Holt CE (2008) NF-protocadherin and TAF1 regulate axon initiation and elongation in vivoThe Journal of Neuroscience, 28 (1): 100-105.

Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung KM, Cogill E, Holt C (2006) Signalling mechanisms underlying Slit2-induced collapse of retinal growth cones. Neuron, 49: 215-228.

Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, Holt C (2005) The transcription factor Engrained-2 guides retinal axons. Nature, 438: 94-98.

Piper M, Salih S, Weinl C, Holt CE, Harris WA (2005) Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation. Nature Neuroscience, 8: 179-186.

View all publications from Dr Piper on ORCiD

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