Migration and differentiation of cortical neurons and associated disorders
Key members involved in this project
- Dr Isabel Martinez Garay
- Ms Melissa Bailey
- Mr Luiz Guidi
The principal neuronal types of the cerebral cortex are the excitatory pyramidal cells, which project to distant targets, and the inhibitory nonpyramidal cells, which are the cortical interneurons. Pyramidal neurons are generated in the cortical neuroepithelium and migrate radially to reach the cortex following an inside-outside gradient. In rodent, only a few nonpyramidal cells are generated in the cortical ventricular zone and interneurons migrate tangentially from the ganglionic eminences.
We are interested in the molecular and cellular mechanisms of cortical cell migration and differentiation. Defects in cortical development have long been associated with disorders like lissencephaly and periventricular heterotopia, but in recent years it has become evident that neuropsychiatric diseases have a developmental component, too. Recent genetic advances have highlighted a number of susceptibility loci in dyslexia and several candidate genes have been identified that seem to be involved in migration. In collaboration with Dr Antonio Velayos-Baeza and Prof Tony Monaco (Wellcome Trust Centre for Human Genetics) we are studying two related genes, KIAA0319 and KIAA0319like. The former is a particularly strong candidate gene for dyslexia, supported by both independent association studies and functional evidence, and the latter is the second member of this protein family. Although both proteins have been characterized biochemically, very little is known about their functions during cortical development. We are using mice that harbor mutations in these genes to characterize their roles in pyramidal neuron migration and differentiation, in an effort to understand the basic mechanisms implicated in this common disorder.
It was recently established that cells of the pallidum also contribute to the formation of the cerebral cortex with interneurons. These cells migrate tangentially through the striatocortical junction to reach the cortex. Cell determination (commitment of progenitor cells to a particular fate) is an essential early step in the development of cell lineages, and current evidence indicates that common mechanisms operate in different tissues to regulate this step. We are particularly interested in the comparative aspects of interneuron generation and migration in reptiles and in examining the differences between primates and rodents (see Evolution of cerebral cortex).