Neuronal Migration

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. Microtubules are composed of tubulin proteins, which are a multi-gene family that we have implicated in neurological disease. For instance, we have shown that mutations in the alpha tubulin TUBA1A cause neuronal migration abnoramlities in mice and lissencephaly in humans (Keays et al, 2007). Furthermore, in collaboration with the Chelly lab we have demonstrated that mutations in TUBB2B cause polymicrogyria, and implicated TUBB5 in microcephaly (Jalgin et al, 2009; Breuss et al 2012).

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 understand how mutations in these genes cause neurodevelopmental disease and the molecular mechanisms underlying neuronal migration we employ the mouse as a model system (Figure 1). We exploit ENU mutagenesis, CRISPR, 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 – I2681-B27 – Knock in Mouse Models and Microtubule Associated Cortical Development Disorders