Keays Group Research
The Molecular Basis of Migration
One of the most remarkable aspects of life, whether it be a single cell or a multicellular organism, is the ability to move. This is even more astounding when one considers that this movement is frequently equipped with directionality. Whether it be a migratory bird that crosses continents, or a cell that inches forward a micrometer at a time, both have a drive, a direction and a destination. What molecular mechanisms underlie this migration? The Keays lab is investigating two very different forms of migration: (1) the migration of neurons; and (2) the migration of animals mediated by magnetic information.
Tubulins in Neuronal Migration and Disease
- Figure 1 (Click to view legend)
Neuronal migration underlies the organisation of the mammalian brain. All neurons that are born in the proliferative ventricular zones migrate to their final destination by extending their primary neurites and translocating their nuclei. This migration is crucial as it determines the destination of a given neuron as well as the circuit in which it operates. Moreover, a host of neurodevelopmental diseases are known to be linked to defective neuronal migration. An example is lissencephaly, a disease that is characterised by a “smooth brain”, epilepsy and mental retardation.
- Figure 2 (Click to view legend)
We have shown that mutations in an alpha tubulin gene (TUBA1A) cause lissencephaly in humans and neuronal migration abnormalities in mice (Keays et al, 2007) (Figure 1). The importance of the tubulin gene family in neuronal migration is further evidenced by our finding that mutations in a beta tubulin gene (TUBB2B) (Jalgin et al, 2009), cause another rare neurdevelopmental disorder known as asymmetric polymicrogyria. To gain insight into the role of different tubulin genes, how they cause disease, and the molecular mechanisms underlying the migration of neurons the Keays lab is employing the mouse as a model system (Figure 2). To complement these murine studies we are taking advantage of next generation sequencing, and in collaboration with a network of clinical colleagues, sequencing the exomes of patients with sporadic neuronal migration disorders. These genetic studies have already identified a number of new disease causing genes which are currently being functionally interrogated.
Circuits, Cells and Molecules in Magnetoreception
- Figure 3 (Click to view legend)
Many species on the planet, whether they be birds, fish or insects rely on the earths magnetic field to guide migration or assist navigation. This remarkable sense is known as magnetoreception. One idea that aims to explain how animals detect magnetic fields is known as the magnetite based theory of magnetoreception. This theory holds that mechanosensitive ion channels coupled to an intracellular compass made of an iron oxide called magnetite (Fe3O4) transduce local magnetic information into a neuronal impulse.
This hypothesis originates from the discovery of magnetotactic bacteria. These aquatic bacteria use the Earth’s magnetic field to direct swimming towards growth-favouring regions in natural waters. It has been shown that magnetotatic bacteria possess organelles called magnetosomes. Magnetosomes consist of membrane-enclosed magnetite crystals that twist into alignment with the Earth’s magnetic field – thereby directing bacterial movement. The theory of magnetite based magnetoreception has been supported by the discovery of magnetite in a range of other organisms that detect and respond to magnetic fields; most notably birds, fish and bees.
The Keays lab is investigating the magnetite based theory of magnetoreception employing the pigeon Columbia livia as a model system. Our current efforts are focused on the upper beak of the pigeon as the ophthalmic branch of the trigeminal nerve is required for magnetoreception in pigeons (Mora et al, 2004). To identify magnetic cells we have built a “magnetoscope” which enables us to identify cells based on their intrinsic magnetic properties. With the recent release of the pigeon genome we are complementing these cellular studies with transcriptomics and molecular profiling. Our ultimate objective is to identify the molecules nature employs to construct a magnetoreceptor.
Video: Magnetotactic bacteria that I collected near Auckland Zoo with Professor Mike Walker. Their swimming direction changes with the orientation of the local magnetic field.
(download Video; 5MB)
Collaborators
Professor Nick Cowan (NYU, New York) – Tubulin biochemistry
Professor Jamel Chelly (Inserm, Paris) – Tubulin and lisssencephaly
Professor Jonathan Flint (Oxford, UK) – Neurodevelopmental mouse mutants