Dr Julian Heng

BSc(Hons) PhD

C J Martin Research Fellow
Honorary Fellow, Centre for Neuroscience (Uni of Melb)
Honorary Lecturer, Dept. of Anatomy & Cell Biology (Uni of Melb)

Brain Development Group

Contact Details

Email:     julian.heng@florey.edu.au

Phone:    +61 (0)3 8344 0417 

Fax:       +61 (0)3 9348 1707

 

Dr Julian Heng is currently a C J Martin Biomedical Research Fellow returning to the Howard Florey Institute after four and a half years at the National Institute for Medical Research (UK). 

Projects are available for Honours and PhD students.

Research Interests

Figure 2. Investigating cortical neuron migration during brain development. Newborn neurons of the germinal zones (VZ/SVZ) migrate in a radial trajectory, move through the intermediate zone (IZ) and populate the cortical plate (CP).
 

The formation of the brain involves the production of many different kinds of neurons that must be positioned very precisely so that they can contact other neurons and integrate into functional neuronal circuits. New neurons are always generated at a distance from their final locations and they must travel along very specific routes in the developing brain to reach these locations (Figure 2, and Heng et al, 2007). This process of neuronal migration is of considerable importance for the correct development of the brain, since mutations in genes that cause migration defects in the cerebral cortex during foetal life often result in severe mental retardation. 

Our goal is to identify the key steps that control neuron production and cell migration within the developing brain, with an emphasis on uncovering novel genes which are essential to these processes.  Through this research, we may be able to better understand the impact of genetic and environmental factors on brain formation and connectivity, and then to apply this knowledge to explain the consequences of abnormal development on subsequent brain function. Our research also focuses on identifying and characterising genes that are associated with the etiology of autism and mental retardation, as well as brain disorders such as schizophrenia and bipolar disorder.

In a related topic, there is strong evidence for a regenerative potential even in adult brain, and this brings about the possibility that we may, in the future, be able to exploit our knowledge of neurogenesis during fetal development to harness this endogenous capacity for adult brain repair to treat serious injuries observed in patients suffering neurodegenerative disorders (such as Parkinson's Disease), or inflicted by physical injury (such as through stroke or brain trauma).

Our approach in the laboratory employs cutting edge techniques to observe the genesis, migration as well as maturation of newborn neurons in the developing brain both in vivo (Figure 3) and in vitro (Figure 4). Student projects are available both for Honours and PhD students (see below).

Figure 3. Embryonic brain cells are labelled with Green Fluorescent Protein (GFP) and their migration is investigated within the developing cerebral cortex.
Figure 4. Embryonic neurons labelled with Green Fluorescent Protein (GFP) are dissociated then cultured in plastic dishes to observe their maturation in vitro. Neurons are identified via with the red cellular marker MAP-2 (microtubule associated protein-2), while their nuclei are counterstained blue with propidium iodide.

Laboratory Techniques

Current Projects

1. What is the molecular basis for neuronal migration?

We have recently shown that the initiation of cell migration by newborn neurons of the developing brain requires the activity the novel GTP-binding protein Rnd2 (Heng et al, 2008), but the underlying mechanism of action remains unclear. Members of the Rnd family of proteins are known to remodel the actin cytoskeleton, and Rnd2 appears to be important for regulating the morphology of migrating neurons, as well as dissociated cortical neurons in vitro (see Figure 5). This project will seek to define the molecular signalling pathways that underlie the role for Rnd2 (as well as its related proteins Rnd1 and Rnd3) in its regulation of migration and morphology in cortical neurons. Knowledge of these mechanisms will lead to a better understanding of how this important developmental process is set out in fetal brain.      

Figure 5. Cortical neurons (arrow) which would normally assume a uni/bipolar morphology tend to assume a multipolar morphology (arrowheads point to neurons with increased numbers of neurites) when Rnd2 expression is knocked-down via siRNA treatment.

2. Transcriptional control of nervous system development

The development of the cerebral cortex involves many steps, including neuron production, cell migration and final maturation of correctly-positioned neurons within fetal brain.  We have discovered that Neurogenin2, a master regulator for neuron production in the cerebral cortex, initiates a proneural transcription factor cascade which is necessary for the generation of excitatory projection neurons of the developing cerebral cortex (Figure 6 and Heng et al, 2008).  This project explores the functional interaction(s) between these transcription factors which are downstream of Neurogenin2, and how they impart the necessary information for proper cortical neuron differentiation as well as their final connectivity.

Figure 6. Control of gene expression and neuronal maturation in the cerebral cortex by the master regulatory gene Neurogenin2. This diagram highlights the sequential activation of downstream transcriptional activators Tbr2, NeuroD1 and NeuroD2 by the proneural bHLH transcription factor Neurogenin2. Through our studies of the Neurogenin2-target gene Rnd2 (Heng et al, 2008), our working hypothesis predicts a cascade of positive regulators (as well as likely negative regulators) that coordinate downstream gene expression for the proper maturation of newborn cortical projection neurons.

3. Identification of novel genes which control neuronal migration and morphology

During fetal brain development, neurons must undergo active cell migration to reach their proper position within developing brain (Figure 2).  Recent reports have underscored the importance of a highly regulated gene expression program for the correct production of migration-promoting factors to control this important developmental process in newborn neurons (reviewed in Merot et al, 2009).  Through our knowledge of the requirement for Neurogenin2 in the specification of the motile-properties of neurons (Hand et al, 2005, Ge et al, 2006, Heng et al, 2008), we are seeking to identify further genetic factors that predetermine the migratory capacity of these neurons as part of their cell-intrinsic programming.

Publications and Articles

Heng, JI, Chariot, A and Nguyen, L. Molecular layers underlying cytoskeletal remodelling during cortical development. Trends in Neurosciences. 2009 In press.

Merot, Y, Reteaux, S and Heng, JI. Molecular mechanisms of projection neuron migration and maturation in the developing cerebral cortex. Seminars in Cell and Developmental Biology. 2009 Aug;20(6):726-34.

Heng, JI, Nguyen, L,Castro, D, Zimmer, C, Armant, O, Skowronska-Krawczyk, D, Bedogni, F, Matter, J-M, Hevner, R, Guillemot, F. Neurogenin2 controls cortical neuron migration through regulation of Rnd2. Nature. 2008 Sep 4;455(7209):114-8.

Zhao, X, Heng, JI, Guardavaccaro, D., Pagano, M., Guillemot, F., Iavarone, A., Lasorella, A. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nature Cell Biology. 2008 May 18.

Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, Guillemot F. p27Kip1 régule indépendamment plusieurs événements cellulaires impliqués dans la production des neurones de projection du cortex cerebral. Bull Mem Acad R Med Belg. 2007;162(5-6):310-4. French.

Heng, JI, Moonen, G., Nguyen, L. Neurotransmitters regulate cell migration in the telencephalon. European Journal of Neuroscience. 2007 Aug;26(3):537-46.

Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, Guillemot F. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes & Development. 2006 Jun 1;20(11):1511-24.

Ge W, He F, Kim KJ, Blanchi B, Coskun V, Nguyen L, Wu X, Zhao J, Heng JI, Martinowich K, Tao J, Wu H, Castro D, Sobeih MM, Corfas G, Gleeson JG, Greenberg ME, Guillemot F, Sun YE. Coupling of cell migration with neurogenesis by proneural bHLH factors. Proceedings of the National Academy of Sciences USA. 2006 Jan 31;103(5):1319-24.

Hand R, Bortone D, Mattar P, Nguyen L, Heng JI, Guerrier S, Boutt E, Peters E, Barnes AP, Parras C, Schuurmans C, Guillemot F, Polleux F. Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron. 2005 Oct 6;48(1):45-62.

Ik Tsen Heng, J., and Tan, S. S. The role of Class I HLH genes in neural development – have they been overlooked? Bioessays 2003; Jul;25(7):709-16.

Heng, J. I. T., and Tan, S. S. Cloning and Characterization of GRIPE, a Novel Interacting Partner of the Transcription Factor E12 in Developing Mouse Forebrain. The Journal of Biological Chemistry. 2002;277:43152-43159.

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