makingtheretina · Principles of retinal neuronal lamination from zebrafish to humans

Neuronal lamination is a hallmark of many diverse brain areas where it is important for efficient circuit formation and neuronal wiring. Despite this significance, the cellular and tissue scale principles that ensure successful and robust lamination are not fully understood. In particular, how cell-tissue interactions and biomechanics influence neuronal lamination is only scarcely explored. To fill this gap, we will use the vertebrate retina with its five neuronal cell types arranged in a highly ordered pattern to investigate the emergence of neuronal lamination. We will initially use the zebrafish system and employ long term light sheet imaging to reveal the migration behaviour of the different retinal neurons. Based on this, transcriptomics approaches will enable the dissection of cellular pathways and extracellular cues involved in neuronal migration and overall lamination. To dissect how biomechanics influence lamination, we will use Brillouin microscopy to explore the influence of changing tissue stiffness on lamination and test the role of differential adhesion. These combined results will be the basis to expand studies to the human system and ex vivo human organoids to generate insights into human retinal development.To date, systematic studies investigating molecular pathways in combination with biophysical parameters to understand brain formation across model systems are rare. Due to our previous expertise, we are in an excellent position to perform such interdisciplinary, integrative and interspecies approach. This will unveil common denominators of retinal neuronal lamination in zebrafish, humans and human organoids and thereby reveal the similarities of retinal development in different species and how developmental programs compare in vivo versus ex vivo.In addition, while this proposal focuses on neural lamination in the retina, findings will also inspire future cross-disciplinary studies investigating neuronal lamination in other parts of the brain.