Periodic Reporting for period 3 - makingtheretina (Principles of retinal neuronal lamination from zebrafish to humans)
Okres sprawozdawczy: 2022-10-01 do 2024-03-31
In most brain regions, developing neurons are arranged into distinct layers giving the mature tissue its stratified appearance. For successful lamination, neurons must move to the correct place after their birth. Defective neuronal migration and lamination can cause pathological brain conditions, including cognitive defects and drug-resistant epilepsy.
While neuronal migration and lamination is well explored in the mammalian neocortex, particularly in rodents, it is less well understood in other parts of the central nervous system. Furthermore, many previous studies have concentrated on cellular mechanisms that drive cortical different neuronal migration modes. While these cellular mechanisms are often understood to the molecular detail, how cell-tissue interplay and particularly the physical environment of migrating cells influence the process is less known.
This is particularly true for the vertebrate retina, an important outpost of the central nervous system responsible for the perception of the visual environment. Here five types of neurons reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Thus, unsurprisingly, neuronal layering defects lead to impaired retinal function. However, how lamination is achieved at the cellular and tissue level and how it is orchestrated in a tissue in which different neurons move concomitantly in different directions is little understood.
This work plan is an important step in understanding this intricate process. Not only do we explore how single cells migrate and orient themselves in a crowded tissue but we also take cell-cell and cell-tissue interplay into account. To this end, we carry out cross-disciplinary studies that involve cell and developmental biologists, experts in biomechanics, theorists and computer scientists. This holistic approach allows us to go beyond the state of the art and integrate and interpret cell and tissue wide phenomena. Our findings are backed up by theoretical models that generate a deeper appreciation of the different phenomena studies. The fact that findings are compared between species, zebrafish and humans as well as human organoids provides the unique opportunity to dissect the nature of species-specific differences in comparison to the in vivo versus an ex vivo environment.
While this project focuses on neural lamination in the retina, findings will also inspire future cross-disciplinary studies that investigate neuronal lamination in other parts of the brain.
While neuronal migration and lamination is well explored in the mammalian neocortex, particularly in rodents, it is less well understood in other parts of the central nervous system. Furthermore, many previous studies have concentrated on cellular mechanisms that drive cortical different neuronal migration modes. While these cellular mechanisms are often understood to the molecular detail, how cell-tissue interplay and particularly the physical environment of migrating cells influence the process is less known.
This is particularly true for the vertebrate retina, an important outpost of the central nervous system responsible for the perception of the visual environment. Here five types of neurons reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Thus, unsurprisingly, neuronal layering defects lead to impaired retinal function. However, how lamination is achieved at the cellular and tissue level and how it is orchestrated in a tissue in which different neurons move concomitantly in different directions is little understood.
This work plan is an important step in understanding this intricate process. Not only do we explore how single cells migrate and orient themselves in a crowded tissue but we also take cell-cell and cell-tissue interplay into account. To this end, we carry out cross-disciplinary studies that involve cell and developmental biologists, experts in biomechanics, theorists and computer scientists. This holistic approach allows us to go beyond the state of the art and integrate and interpret cell and tissue wide phenomena. Our findings are backed up by theoretical models that generate a deeper appreciation of the different phenomena studies. The fact that findings are compared between species, zebrafish and humans as well as human organoids provides the unique opportunity to dissect the nature of species-specific differences in comparison to the in vivo versus an ex vivo environment.
While this project focuses on neural lamination in the retina, findings will also inspire future cross-disciplinary studies that investigate neuronal lamination in other parts of the brain.
We have shown that neuronal migration and resulting lamination in the retina is much more complex than previously assumed. We also showed that it requires the intricate coordination between migrating cells and the surrounding tissue. As migration and lamination coincides with ongoing proliferation, it needs to be ensured that neither of the processes is blocked by the respective other cell type. These findings will lead to new paradigms and position neuronal migration, for now in the retinal context, as an important factor of overall morphogenesis coordination, beyond its canonical role of positioning cells at the place at which they will later function.
We so far have shown that this intricate interplay is important for successful migration and lamination for the horizontal and photoreceptor cells in the retina.
For the horizontal cells, we unravelled a previously unknown migration modes in central nervous system development which is ameboid-like migration. This type of migration has been shown to be at play mainly for cells of the immune system and during wound healing but not yet prominently duing brain formation. Our studies also showed that the efficiency of this type of migration crucially depends on physical cellular properties, the direct surrounding environment as well as overall tissue architecture.
Photoreceptor cells undergo an intriguing bidirectional migration mode that is initially reminiscent of somal translocation. Interestingly, depending on direction, different cytoskeletal machineries are employed, an atypical way to move the cell body. Even more interestingly, we find that the bidirectional migration does actually not lead to a net displacement of cells, as they return to the place where they were born. Instead, this counterintuitive migration phenomenon serves to coordinate growth and lamination of the developing retina. Precisely, it allows progenitor cells to still undergo apical divisions (important for correct tissue maturation) while photoreceptors are temporarily moved out of the way. As concomitant growth and differentiation are a hallmark of many developing tissues, this finding paves the way for starting to look for other such phenomena in the retina and beyond.
Together, our cross-disciplinary approaches opened new areas to study growth, migration and lamination phenomena in the retina that we are keen to follow up upon during the remainder of the project.
We so far have shown that this intricate interplay is important for successful migration and lamination for the horizontal and photoreceptor cells in the retina.
For the horizontal cells, we unravelled a previously unknown migration modes in central nervous system development which is ameboid-like migration. This type of migration has been shown to be at play mainly for cells of the immune system and during wound healing but not yet prominently duing brain formation. Our studies also showed that the efficiency of this type of migration crucially depends on physical cellular properties, the direct surrounding environment as well as overall tissue architecture.
Photoreceptor cells undergo an intriguing bidirectional migration mode that is initially reminiscent of somal translocation. Interestingly, depending on direction, different cytoskeletal machineries are employed, an atypical way to move the cell body. Even more interestingly, we find that the bidirectional migration does actually not lead to a net displacement of cells, as they return to the place where they were born. Instead, this counterintuitive migration phenomenon serves to coordinate growth and lamination of the developing retina. Precisely, it allows progenitor cells to still undergo apical divisions (important for correct tissue maturation) while photoreceptors are temporarily moved out of the way. As concomitant growth and differentiation are a hallmark of many developing tissues, this finding paves the way for starting to look for other such phenomena in the retina and beyond.
Together, our cross-disciplinary approaches opened new areas to study growth, migration and lamination phenomena in the retina that we are keen to follow up upon during the remainder of the project.
What defines our work is its cross-disciplinary nature. We work with scientists across disciplines from developmental and cell biology, to theory, mathematical statistics and computer science. This elevates communication and overall leads to a deeper understanding of biological processes beyond the state of the art. All contributors benefit from these discussions and collaborations. Thus, our work will lead to new and important insights on the cell-tissue interplay of neuronal lamination during retinogenesis.
Experimentally, we implemented a human organoid system in our workflow that recapitulates early stages of neuronal lamination. This gives us the unique possibility to compare retinal formation between species, particularly between zebrafish and humans. Furthermore, it also, independently of species specificaltions, allows us to compare in vivo to ex vivo development. This is potentially important to improve the generation of human organoids for long term therapeutic strategies, a goal that while it lies beyond this workplan, our project will pave teh way and add knowledge to achieve that.
Experimentally, we implemented a human organoid system in our workflow that recapitulates early stages of neuronal lamination. This gives us the unique possibility to compare retinal formation between species, particularly between zebrafish and humans. Furthermore, it also, independently of species specificaltions, allows us to compare in vivo to ex vivo development. This is potentially important to improve the generation of human organoids for long term therapeutic strategies, a goal that while it lies beyond this workplan, our project will pave teh way and add knowledge to achieve that.