Neuronal migration and magnetoreception
Tubulins in neuronal migration and disease
Neuronal migration underlies the organization 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 because it not only determines the destination of a given neuron, but also the circuit in which it operates. Moreover, a host of neurodevelopmental diseases are known to be linked with defective neuronal migration. One example is lissencephaly, a disease that is characterized by a “smooth brain”, epilepsy, and mental retardation. We have shown that mutations in the 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 cortical development is further illustrated by our finding that mutations in the beta tubulin gene TUBB2B cause polymicrogyria, a disease characterized by excessive folding of the cortex (Jalgin et al., 2009). Most recently we have shown that mutations in TUBB5 cause a reduction in brain size in humans, and perturb both migration and neurogenic division in mice (Breuss et al., 2012).
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. We use ENU mutagenesis, as well as transgenic methods to generate new models for human disease. 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.
Molecular and cellular basis of magnetoreception
Many species on the planet, whether they are birds, fish or insects, rely on the Earth’s 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 known as magnetite (Fe3O4) transduce local magnetic information into a neuronal impulse.
We are using the rock pigeon Columba livia as a model (Figure 2). Previous studies have asserted that pigeons employ a magnetite-containing sensory apparatus located at six specific loci in the skin of the beak. We have shown that this established dogma is false, and in reality clusters of iron-rich cells in the beak of pigeons are macrophages; they are not magnetosensitive neurons (Treiber, Salzer et al., 2012). The field is now engaged in a renewed search for the true magnetoreceptive cells. Where are the magnetosensory cells in avian species?
Recent electrophysiological studies have identified a population of neurons in the vestibular nuclei of pigeons that respond to magnetic vectors of a specific orientation and intensity (Wu and Dickman, 2012). These results strongly suggest that a population of unidentified magnetosensory cells lie in the inner ear of pigeons. Employing histological techniques, we identified sensory hair cells that contain a single iron-rich organelle (Figure 3). This organelle is located directly beneath the stereocilia and is embedded in the actin-rich cuticular plate. We have shown that this structure is present in a wide range of avian species, but is not found in rodents, fish, or humans (Lauwers, Pichler et al., 2013). Our current work is focused on elucidating the function of this organelle, specifically whether it plays a direct or indirect role in magnetoreception.
Professor Nick Cowan (NYU, New York) – Tubulin biochemistry
Professor Jamel Chelly (Inserm, Paris) – Tubulin and lisssencephaly
Professor Jonathan Flint (Oxford, UK) – Neurodevelopmental mouse mutants
- Gstrein, T., Edwards, A., Přistoupilová, A., Leca, I., Breuss, M., Pilat-Carotta, S., Hansen, AH., Tripathy, R., Traunbauer, AK., Hochstoeger, T., Rosoklija, G., Repic, M., Landler, L., Stránecký, V., Dürnberger, G., Keane, TM., Zuber, J., Adams, DJ., Flint, J., Honzik, T., Gut, M., Beltran, S., Mechtler, K., Sherr, E., Kmoch, S., Gut, I., Keays, DA. (2018). Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.Nat Neurosci. 21(2):207-217
- Edelman, NB., Fritz, T., Nimpf, S., Pichler, P., Lauwers, M., Hickman, RW., Papadaki-Anastasopoulou, A., Ushakova, L., Heuser, T., Resch, GP., Saunders, M., Shaw, JA., Keays, DA. (2015). No evidence for intracellular magnetite in putative vertebrate magnetoreceptors identified by magnetic screening. Proc Natl Acad Sci U S A. 112(1):262-7
- Lauwers, M., Pichler, P., Edelman, NB., Resch, GP., Ushakova, L., Salzer, MC., Heyers, D., Saunders, M., Shaw, J., Keays, DA. (2013). An iron-rich organelle in the cuticular plate of avian hair cells. Curr Biol. 23(10):924-9
- Treiber, CD., Salzer, MC., Riegler, J., Edelman, N., Sugar, C., Breuss, M., Pichler, P., Cadiou, H., Saunders, M., Lythgoe, M., Shaw, J., Keays, DA. (2012). Clusters of iron-rich cells in the upper beak of pigeons are macrophages not magnetosensitive neurons. Nature. 484(7394):367-70
- Keays, DA., Tian, G., Poirier, K., Huang, GJ., Siebold, C., Cleak, J., Oliver, PL., Fray, M., Harvey, RJ., Molnár, Z., Piñon, MC., Dear, N., Valdar, W., Brown, SD., Davies, KE., Rawlins, JN., Cowan, NJ., Nolan, P., Chelly, J., Flint, J. (2007). Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell. 128(1):45-57