Cell-cell interactions in the regulation of neural progenitor fate: the role of PCDH19

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The brain is a complex, yet highly ordered structure serving as the control centre for all vertebrates and some invertebrates. In mammals, one region of the brain, designated the cerebral neocortex, is particularly important for elaborate processes such as memory, attention, thoughts, perception and language. Neurons in the mammalian neocortex are distributed in specific layers and have distinct morphological and functional properties. These neurons are generated during development by specific cells, called neural progenitors. These progenitors need to produce the correct amount of neurons for each of the layers, and they do it sequentially. They first produce neurons for the deepest layer, then for the layer on top of that, and so on until all layers are generated. This means that progenitors need to maintain a balance between giving rise to neurons and maintaining their own population, to avoid getting depleted before all neurons are produced. Progenitors can divide in two different ways: symmetrically and asymmetrically. Symmetric divisions produce two identical daughter cells, either two progenitors or two neurons. Asymmetric divisions give rise to two different cells: one progenitor and one neuron. At very early stages in the formation of the cortex, progenitors divide symmetrically to increase their numbers. But at some point they need to change to asymmetric divisions to start producing neurons. How progenitors make this decision is currently not understood. My laboratory is investigating the mechanisms that control development of the cerebral cortex. We have recently found that one cell-cell adhesion protein, protocadherin 19 (PCDH19), is involved in the regulation of neural progenitor behaviour. PCDH19 is mutated in a human disorder leading to epilepsy and varying degrees of cognitive impairment in very young girls. This molecule is present in neural progenitors around the time of the symmetric to asymmetric division switch. We have found that progenitors with PCDH19 produce neurons at different rates when they are alone than when they coexist with progenitors that lack this protein. The same is true for the PCDH19-deficient progenitors. This suggests that communication between cells is important to regulate progenitor behaviour and that we can use PCDH19 to investigate this process. We will first determine if the changes that we have seen at embryonic day E11.5 are maintained in time and how they affect overall neuronal production. We will then analyse the dividing progenitor cells to find out what makes the progenitors with PCDH19 different from the ones without this protein. Finally, we will use both direct and unbiased approaches to figure out which molecules and signalling pathways are responsible for the differential behaviour between the two progenitor types. We will investigate particular molecular pathways that have been shown to play a role in the maintenance of progenitor cells. At the same time, we will carry out an analysis of all genes expressed by PCDH19-positive and -negative progenitors to assess other potential differences in an unbiased way.These experiments will provide valuable information to explain how progenitors decide to start producing neurons, but they will also reveal how cell-cell communication influences this process. This information is crucial to understand how brains are formed correctly, an essential knowledge when studying neurodevelopmental disorders.