Don van Meyel
Email: don [dot] vanmeyel [at] mcgill [dot] ca
Tel.: 514-934-1934 ext. 42995
Associate Professor | Neurology & Neurosurgery, Medicine (Dept. & Faculty)
Researcher | Research Institute of the McGill University Health Centre
Associate Member | Dept. of Biology
We encourage applications from motivated post-docs and students who are interested in our research.
Neurons and glial cells are the two major cell types in the human central nervous system (CNS), and interactions between them are vital for the CNS to develop and function properly. In addition, signaling between neurons requires the establishment of precise and complex intercellular connections through the patterned development of axons and dendrites. Research themes in the van Meyel lab focus on:
- The importance of neuron-glial interactions during development and how perturbations of these processes can contribute to neurological diseases.
- The patterned growth and guidance of axons and dendrites and how improved understanding of the underlying mechanisms can be used to promote repair in the injured or diseased CNS.
- Molecular mechanisms of the Hedgehog (Hh) signaling pathway, which is vital for nervous tissue development and is misregulated in pediatric brain tumors.
To explore these issues, we use the advanced genetics and molecular tools available for the fruit fly, Drosophila melanogaster. Drosophila has been well-studied and many functional, morphological and molecular features of neurons and glia are well conserved between mammals and insects. Using strategies that include genetics, molecular biology, biochemistry and confocal imaging, we investigate molecular and cellular mechanisms of neuron-glial interactions, axon guidance and dendrite patterning in relation to CNS development and function.
Interactions between neurons and glial cells are critical for the development, function and maintenance of the CNS. However, our understanding of the differentiation and functional diversity of glial cell subtypes is limited, and few molecular signals that regulate communication between neurons and glia have been identified. We are using Drosophila to address the following three questions: 1) How do glial cell subtypes emerge from intrinsic genetic programs? 2) How do neurons contribute to the differentiation of glial cell subtypes? and 3) How do these glial subtypes serve neuronal function?
To study glial cell differentiation and neuron-glial interactions, we focus on an interesting class of Drosophila glia called the longitudinal glia (LG). In late embryos, LG can be divided into subtypes based on molecular markers, but little is known about their mature properties and functions in larvae. We are currently using genetic approaches to selectively label and identify each LG cell in L1 larvae, in order to precisely examine their morphology and organization. We are also studying how communication between neurons and LG contributes to the subdivision of LG into distinct subtypes. This is in part due to a particular molecular signaling pathway mediated through the Notch receptor molecule.
We are also studying interactions between neurons and glial cells contribute to nervous system function, and how perturbations of these interactions can contribute to neurological diseases. Glutamate is an important neurotransmitter in humans as well as in fruit flies, and tight control of extracellular glutamate levels is crucial to avoid glutamate over-excitation, toxicity and neural cell death. Most extracellular glutamate is safely moved into glial cells by excitatory amino acid transporters (EAATs). Expression of EAATs is dysregulated in epilepsy, EAAT mutant mice exhibit spontaneous seizures, and humans with mutations in the EAAT known as SLC1A3/GLAST suffer seizures in addition to episodic ataxia and hemiplegic migraine. Despite this importance for CNS pathologies, the mechanisms of EAAT regulation and pathogenesis are poorly understood. Drosophila is an advanced genetic model with a single high-affinity glutamate transporter termed Eaat1, and we are using genetic approaches in fruit flies to explore the pathologic consequences of EAAT dysfunction, and to identify factors that regulate EAATs and influence over-excitement by glutamate in vivo. This research could lead to progress in understanding and treating more common CNS diseases like epilepsy in which excess glutamate is thought to be a contributing factor.
Dendrites are specialized tree-like structures that allow neurons to receive sensory and synaptic input within the nervous system. Diseases associated with mental retardation, including Down Syndrome, Rett Syndrome and Fragile-X Syndrome among others, are often associated with the disruption of the normal architecture of neuronal dendrites. This may result from altered dendrite development, and the goal of our research is to uncover novel cellular and molecular mechanisms that underlie the tree-like patterns of growth, branching and targeting of dendrites. Dendrites in Drosophila are remarkably similar to dendrites in humans, displaying many of the same molecular and functional properties. We recently used this model to discover that two proteins, called Lola and Turtle, are essential for specific aspects of the growth and branching of dendritic trees. We hypothesize that Lola, a transcription factor, regulates the abundance of factors that control the underlying molecular “skeleton” of dendrites and the delivery of other essential building materials. Turtle is a member of the immunoglobulin superfamily (IgSF) of proteins and we hypothesize that it acts at the surface of dendrites to steer or stabilize growing branches. In ongoing research, we are 1) investigating how Lola regulates the cytoskeleton of dendritic trees and the distribution of building materials to them, and 2) discovering cellular and molecular mechanisms by which Turtle influences growing dendrite branches.
Hedgehog (Hh) is a secreted morphogen that governs neural fate specification, neural precursor proliferation, and axon guidance in developing nervous systems. Reception of Hh at the cell surface has long been thought to be mediated by Ptc, a 12-pass transmembrane protein, which ordinarily inhibits the pathway when Hh is absent. Binding of Hh to Ptc is thought to inhibit Ptc and thereby initiate transduction of the pathway. The interaction between Hh and Ptc is also believed to be essential to sequester Hh and thus limit its spatial range of influence. In collaboration with the lab of Dr. Frederic Charron, we have found that additional factors at the cell surface play an important role in the reception of Hh: Ihog and Boi are two functionally redundant type 1 transmembrane proteins of the immunoglobulin superfamily that are required for pathway activation and capable of binding both Hh and Ptc. This raises the possibility that Ihog/Boi and Ptc form a complex required for the reception of the Hh signal. However, the mechanism underlying the requirement for Ihog and Boi in the inhibition of Ptc is not known.
Despite its importance in many developmental events in diverse species, the molecular signaling mechanism underlying the function of Hh is still not fully elucidated. Our work aims to better understand the Hh receptor complex by using genetic approaches to clarify the involvement Ihog/Boi and Ptc. A long-term goal is to understand mechanisms by which Ihog, Boi and Hh contribute to the development of the CNS, and so expand our limited view of the principles upon which the CNS is organized.