Abstract
The intricate patterns of cell migration that are found throughout development are generated through a vast array of guidance cues. Responding integratively to distinct, often conflicting, migratory signals is probably crucial for cells to reach their correct destination. Pax6 is a master transcription factor with key roles in neural development that include the control of cell migration. In this study, we have investigated the ability of cells derived from cortical neurospheres from wild-type (WT) and Pax6−/− mouse embryos to integrate diverging guidance cues. We used two different cues, either separately or in combination: substratum nanogrooves to induce contact guidance, and electric fields (EFs) to induce electrotaxis. In the absence of an EF, both WT and Pax6−/− cells aligned and migrated parallel to grooves, and on a flat substrate both showed marked electrotaxis towards the cathode. When an EF was applied in a perpendicular orientation to grooves, WT cells responded significantly to both cues, migrating in highly oblique trajectories in the general direction of the cathode. However, Pax6−/− cells had an impaired response to both cues simultaneously. Our results demonstrate that these neurosphere derived cells have the capacity to integrate diverging guidance cues, which requires Pax6 function.
Highlights
The integration of multiple, diverging guidance cues is likely to be a key feature of cell migration in vivo, as cells have to respond for instance to gradients of soluble attractant molecules as well to the adhesive and topographical features of the surrounding extracellular matrix and neighbouring cells [1]
We have investigated the behaviour of wild-type (WT) and Pax6−/− cells derived from cortical neurospheres under contact guidance and electric fields (EFs) cues
For both WT and Pax6−/− cells plated in flat quartz, the average orientation angle was close to 45°, indicative of unbiased migration, whereas it was significantly higher in quartz with vertical grooves, indicative of cell trajectories highly aligned to grooves
Summary
The integration of multiple, diverging guidance cues is likely to be a key feature of cell migration in vivo, as cells have to respond for instance to gradients of soluble attractant molecules as well to the adhesive and topographical features of the surrounding extracellular matrix and neighbouring cells [1]. To migrate along processes of neighbouring cells, indicating that they use topographical features of 2 their microenvironment as guidance cues [5]. A deeper understanding of how these different guidance cues are integrated is likely to contribute to improve brain repair therapies that rely on neural stem cell migration, as well as being central to elucidating the regulation of cell migration during neural development
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