Final Report Summary - NEUROMIGRATION (Role of Ebf3 in the distribution of Cajal-Retzius cells)
The organisation of the mammalian neocortex into a six-layered structure is one of the most important features of the brain. Proper assembly of the neocortex requires precise regulation of neuronal migration and abnormalities in this process can result in severe neurological diseases. This complex architecture is set up during embryonic development. During this process, the distinct neuronal populations are produced sequentially, so early-generated neurons assemble in a structure that undergoes a drastic developmental growth. One very important question is how the positioning of these firsts neurons is maintained during brain expansion, and it is virtually unknown.
Cajal-Retzius (CR) cells are one of these early-born neuronal populations; they migrate from focal sources and cover the entire cortical surface from embryonic day 12.5 in the mouse embryo (Takiguchi-Hayashi et al., 2004; Yoshida et al., 2006; Bielle at al., 2005; Imayoshi et al., 2008). Once CR cells have covered the cerebral cortex throughout embryogenesis, they regulate the lamination and regionalisation of underlying circuits, which are built over an extended time-period (Supèr et al., 1997; Griveau et al., 2010). During the last years, a great effort has been done to unravel how CR cells migrate from their sources and cover the cortical surface (Borrell and Marín, 2006; Ceci et al., 2010 and Kwon et al., 2010; Griveau et al., 2010). Nevertheless, a more intriguing question, related with the problematic exposed above, arises at this point: as all CRs are born at the same time, early in neurogenesis, how these cells maintain their homogeneous distribution in the cortical surface, fundamental for the final cortical organisation and/or aeralisation (Supèr et al., 1997; Griveau et al., 2010), throughout all embryonic development?
The main goal of this project was to understand the mechanisms controlling the distribution of CR cells in the marginal zone of the cortex while its surface is growing, in order to achieve their fundamental functions in cortical organisation and specification.
We have showed evidence that a secondary active migration is required to maintain CR cells distribution during the embryonic growth of the cerebral cortex. Using mouse genetics and imaging, we have found that maintenance of CR cells distribution throughout growth requires a secondary wave of active migration from a CR cells transient reservoir located in the prospective olfactory cortex.
Furthermore, we have shown that this secondary CR cells migration is regulated by the transcription factor Ebf3, which inactivation does not affect early CR cells migration, but leads to a striking unbalance in their late distribution over the cerebral cortex.
Finally, we have studied the biological signification of the secondary wave of migration of CR cells from their reservoir in the lateral forebrain, using the Ebf3 mutant mice, where this event is affected. We have seen that in areas where the concentration of CR cells is not correct, the underlying cortex is defective, meaning that the correct distribution of CR cells at late stages of embryonic development is essential for the organisation of the underlying cortex.
Thus, our results reveal a novel role for neuronal migration in the homeostasis of neural circuits during developmental growth and contribute to the understanding of the multiple roles of CR cells during mammalian embryogenesis.
Cajal-Retzius (CR) cells are one of these early-born neuronal populations; they migrate from focal sources and cover the entire cortical surface from embryonic day 12.5 in the mouse embryo (Takiguchi-Hayashi et al., 2004; Yoshida et al., 2006; Bielle at al., 2005; Imayoshi et al., 2008). Once CR cells have covered the cerebral cortex throughout embryogenesis, they regulate the lamination and regionalisation of underlying circuits, which are built over an extended time-period (Supèr et al., 1997; Griveau et al., 2010). During the last years, a great effort has been done to unravel how CR cells migrate from their sources and cover the cortical surface (Borrell and Marín, 2006; Ceci et al., 2010 and Kwon et al., 2010; Griveau et al., 2010). Nevertheless, a more intriguing question, related with the problematic exposed above, arises at this point: as all CRs are born at the same time, early in neurogenesis, how these cells maintain their homogeneous distribution in the cortical surface, fundamental for the final cortical organisation and/or aeralisation (Supèr et al., 1997; Griveau et al., 2010), throughout all embryonic development?
The main goal of this project was to understand the mechanisms controlling the distribution of CR cells in the marginal zone of the cortex while its surface is growing, in order to achieve their fundamental functions in cortical organisation and specification.
We have showed evidence that a secondary active migration is required to maintain CR cells distribution during the embryonic growth of the cerebral cortex. Using mouse genetics and imaging, we have found that maintenance of CR cells distribution throughout growth requires a secondary wave of active migration from a CR cells transient reservoir located in the prospective olfactory cortex.
Furthermore, we have shown that this secondary CR cells migration is regulated by the transcription factor Ebf3, which inactivation does not affect early CR cells migration, but leads to a striking unbalance in their late distribution over the cerebral cortex.
Finally, we have studied the biological signification of the secondary wave of migration of CR cells from their reservoir in the lateral forebrain, using the Ebf3 mutant mice, where this event is affected. We have seen that in areas where the concentration of CR cells is not correct, the underlying cortex is defective, meaning that the correct distribution of CR cells at late stages of embryonic development is essential for the organisation of the underlying cortex.
Thus, our results reveal a novel role for neuronal migration in the homeostasis of neural circuits during developmental growth and contribute to the understanding of the multiple roles of CR cells during mammalian embryogenesis.