An early cell shape transition drives evolutionary expansion of the human forebrain
Posted on: 31 July 2020
Preprint posted on 4 July 2020
Article now published in Cell at http://dx.doi.org/10.1016/j.cell.2021.02.050
How Humans Got Big Brains: A delayed cell-state transition in neurogenesis leads to a larger human brain
Selected by Monica Tambalo, Teresa Rayon, Maiko KitaokaCategories: developmental biology, evolutionary biology, neuroscience
Background
How has the human brain evolved its unique features? Such a fascinating question remains yet widely unexplored. Among the human brain’s remarkable features, its size is perhaps one of the most evident, with roughly a 3-fold increase in human brain size compared to chimpanzee and gorilla. A conspicuous amount of studies, mainly using rodent model systems, have contributed to our current understanding of brain embryonic development. Such approaches are excellent to teach us about conserved mechanisms but are not suitable for informing on human specific brain features and primate evolution.
A revolutionary approach to study human brain development and its evolution has been the advent of human brain organoids derived from human pluripotent stem cells [1],[2], and the invaluable possibility of extending this approach to virtually any species.
A fundamental process in brain development is neurogenesis. Within the cerebral cortex a neurogenic precursor, also known as neuroepithelial (NE) cell, is characterized by a columnar morphology and divides symmetrically during its proliferative phase. This proliferation is essential for the enlargement of the neocortex in primates. NE cells are highly epithelial, with tight and adherens junctions at their apical surface. NE progenitors will then transition into neurogenic radial glia (RG) by losing epithelial features, thinning and elongating the bipolar processes, and switching to asymmetric cell divisions, where one daughter cell self-maintains itself as RG and the other starts the neurogenic differentiation. This mechanism has been mainly studied using murine models while little is known about how it works in apes. Correlative evidence points to early changes in NE behaviour as a key mechanism for human cortical expansion, however direct evidence is poor.
To address directly this issue, Benito-Kwiecinski, Giandomenico, and colleagues [3] derived brain organoids from human, gorilla and chimpanzee and directly compared their neurogenetic properties, prior to neuron formation. This approach has given the authors the advantage of manipulating candidate genes and the ability to address their involvement in human and ape brain evolution.
(Top panels) 5-week organoids stained for neural progenitor marker SOX2 (red), dorsal telencephalic/intermediate progenitor marker TBR2 (grey), neuronal markers TUJ1 (human) and HuCD (gorilla) in yellow, and DAPI (blue) showing human derived organoids become larger in overall size than gorilla and chimpanzee organoids. Scale bar: 1 mm. From Figure 1A.
(Lower panels) Schematic summarizing the morphological changes in neural progenitor cells observed in human and gorilla organoids. Progenitor cells of both species undergo a gradual transition from NE to tNE to RG-like shapes. Human cells maintain columnar NE-characteristics for a longer period while gorilla cells show tNE morphologies (blue background) earlier than human. From Figure 2H.
Key points
- The authors developed comparable human, gorilla and chimpanzee brain organoids to study NE development prior to the onset of neurogenesis. Perhaps as expected, human brain organoids were consistently larger than the gorilla or chimp organoids.
- Human organoids show an enlarged ventricular apical surface at early stages of NE expansion, before the onset of neurogenesis.
- The transition from NE (non neurogenic) to RG (neurogenic) in human and ape occurs during several days, and ape NE cells make this transition more rapidly than human.
- Cell shape changes occur before the change in cell identity and before the onset of neurogenesis.
- Identification of a new intermediate cell morphology state, the tNE.
- By comparing RNA-seq data from each species, they focused on the differential expression of the ZEB2 gene, particularly due to its well-known role as a key mediator of the EMT transition and found that the ZEB2 gene drives the NE to RG transition.
- Delayed onset of ZEB2 expression extends the NE stage, compared to ape, and may be a major contributor to neocortical expansion in humans
- They generated an inducible-ZEB2 human brain organoid, demonstrating the powerful advantages of organoids to allow unprecedented control to manipulate genes involved in neurogenesis. By overexpressing human ZEB2 prematurely to match the expression levels and timing of gorilla organoids, the authors could trigger an earlier NE transition that led to a nonhuman, ape-like organoid morphology! This suggests that ZEB2 is a key regulator of species-specific brain development.
Things we like
This work elegantly demonstrates how the evolution of the neocortex can be studied systematically and quantitatively comparing stem cell models/organoids across species, providing perturbations that wouldn’t be feasible in human embryos. Previous 2D and 3D comparisons using stem cell models of primate cortical development had primarily focused on the differences in composition and proliferation rates of radial glial cells (RG) of macaque, human and chimpanzees [4]–[7]. Instead, this work centres its attention on the role of NE cells in cortical expansion for the first time and adds gorilla stem cells to the primate cerebral organoid zoo. Finally, we really appreciate that this work applies a classical embryology approach to organoids, where the authors start from a morphological observation and have begun to pin down the molecular mechanism.
Questions for the authors
Q1. How complex was it to establish reliable differentiation protocols for human, gorilla and chimpanzee brain organoids? And how consistent were the phenotypes observed across cell lines?
Q2. Is ZEB2 regulated differently in gorilla vs human vs chimp? How so? Ie, what triggers its expression, and how might this be regulated in a species-specific way?
Q3. Mutations in the ZEB2 gene cause Mowat-Wilson syndrome. Do the authors think that the early role that they uncovered for ZEB2 is related to the microcephaly and intellectual disability of the patients?
Q4. Mutations in the ZEB2 gene cause Mowat-Wilson syndrome. Do the authors think that the early role that they uncovered for ZEB2 is related to the microcephaly and intellectual disability of the patients?
Q5. Considering the exceptional current times, it has been challenging for everyone to work from home at a usual pace. How was the process of writing this preprint during lockdown?
References
- Lancaster, M. A.; Knoblich, J. A. Generation of Cerebral Organoids from Human Pluripotent Stem Cells. Nat. Protoc. 2014, 9 (10), 2329–2340. https://doi.org/10.1038/nprot.2014.158.
- Lancaster, M. A.; Renner, M.; Martin, C. A.; Wenzel, D.; Bicknell, L. S.; Hurles, M. E.; Homfray, T.; Penninger, J. M.; Jackson, A. P.; Knoblich, J. A. Cerebral Organoids Model Human Brain Development and Microcephaly. Nature 2013, 501 (7467), 373–379. https://doi.org/10.1038/nature12517.
- Benito-Kwiecinski, S.; Giandomenico, S. L.; Sutcliffe, M.; Riis, E. S.; Freire-Pritchett, P.; Kelava, I.; Wunderlich, S.; Martin, U.; Wray, G. A.; Lancaster, M. A. An Early Cell Shape Transition Drives Evolutionary Expansion of the Human Forebrain. bioRxiv 2020, 2020.07.04.188078. https://doi.org/10.1101/2020.07.04.188078.
- Neurogenesis, C.; Fiddes, I. T.; Lodewijk, G. A.; Mooring, M.; Salama, S. R.; Jacobs, F. M. J.; Haussler, D.; Fiddes, I. T.; Lodewijk, G. A.; Mooring, M.; Bosworth, C. M.; Ewing, A. D. Human-Specific NOTCH2NL Genes Affect Notch Article Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis. Cell 2018, 173 (6), 1356-1369.e22. https://doi.org/10.1016/j.cell.2018.03.051.
- Otani, T.; Marchetto, M. C.; Gage, F. H.; Simons, B. D.; Livesey, F. J.; Otani, T.; Marchetto, M. C.; Gage, F. H.; Simons, B. D.; Livesey, F. J. 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size Article 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Stem Cell 2016, 18 (4), 467–480. https://doi.org/10.1016/j.stem.2016.03.003.
- Suzuki, I. K.; Gacquer, D.; Heurck, R. Van; Polleux, F.; Detours, V.; Vanderhaeghen, P. Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta / Notch Regulation Article Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta / Notch Regulation. 2018, 1370–1384. https://doi.org/10.1016/j.cell.2018.03.067.
- Pollen, A. A.; Bhaduri, A.; Andrews, M. G.; Nowakowski, T. J.; Meyerson, O. S.; Mostajo-Radji, M. A.; Di Lullo, E.; Alvarado, B.; Bedolli, M.; Dougherty, M. L.; Fiddes, I. T.; Kronenberg, Z. N.; Shuga, J.; Leyrat, A. A.; West, J. A.; Bershteyn, M.; Lowe, C. B.; Pavlovic, B. J.; Salama, S. R.; Haussler, D.; Eichler, E. E.; Kriegstein, A. R. Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution. Cell 2019, 176 (4), 743-756.e17. https://doi.org/10.1016/j.cell.2019.01.017.
doi: https://doi.org/10.1242/prelights.23633
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3 years
Sheila Garcia-Rosa
How long it took to develop this work, from the experimental design to the final experiment?