neuronal-migration-top

Neuronal migration is a phenomenon that underlies the organisation of the mammalian brain. All neurons that are born in the proliferative ventricular zone (VZ) migrate to their final destination either radially or tangentially (Ayala et al. 2007). The process of migration involves extensive morphological changes requiring the advancement of a leading neurite, somal translocation of the nucleus into that neurite, and the retraction of the trailing processes (Lambert de Rouvroit and Goffinet 2001). This sophisticated cellular journey relies on a myriad of intracellular and extracellular signalling factors that include REELIN, DAB1, VLDLR, and DCX, which converge on the microtubule cytoskeleton. We have previously shown that mutations in an alpha tubulin gene (TUBA1A) cause severe neuronal migration defects in mice (Keays et al, 2007), and neurodevelopmental disease in humans. The importance of the tubulin gene family in neuronal migration is further evidenced by our finding that mutations in the beta tubulin genes TUBB2B and TUBB5 (Jalgin et al, 2009; Breuss et al 2012), cause structural brain abnormalities. Most recently, TUBA1A and TUBB2B have also been implicated in autism spectrum disorders  (Neale et al., 2012; Pinto et al., 2010).

Figure 1: The Jenna mutant mouse. This mouse harbours a S140G mutation in the Tuba1a gene which results in defect neuronal migration during development. As a consequence the Jenna mouse is characterised by abnormal lamination of the hippocampus that is accompanied deficits in cognitive tasks.

Figure 1: The Jenna mutant mouse. This mouse harbours a S140G mutation in the Tuba1a gene which results in defect neuronal migration during development.

To gain insight into the role of different tubulin genes and the molecular mechanisms underlying the migration of neurons the Keays lab is employing the mouse as a model system (Figure 1). We are employing ENU mutagenesis, as well as transgenic methods to interrogate the molecular pathway that enables a neuron to trek across the developing brain.

Collaborators: Dr Julian Heng (Monash), Professor Jamel Chelly (Paris), Professor Nick Cowan (NYU)
Funded by: FWF I914, Genetics of cortical gyral dysgenesis.