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Review
. 2021 Feb;59(1-2):e23405.
doi: 10.1002/dvg.23405. Epub 2020 Dec 27.

Xenopus leads the way: Frogs as a pioneering model to understand the human brain

Cameron R T Exner  1 , Helen Rankin Willsey  1
Affiliations
Review

Xenopus leads the way: Frogs as a pioneering model to understand the human brain

Cameron R T Exner et al. Genesis. 2021 Feb.

Abstract

From its long history in the field of embryology to its recent advances in genetics, Xenopus has been an indispensable model for understanding the human brain. Foundational studies that gave us our first insights into major embryonic patterning events serve as a crucial backdrop for newer avenues of investigation into organogenesis and organ function. The vast array of tools available in Xenopus laevis and Xenopus tropicalis allows interrogation of developmental phenomena at all levels, from the molecular to the behavioral, and the application of CRISPR technology has enabled the investigation of human disorder risk genes in a higher-throughput manner. As the only major tetrapod model in which all developmental stages are easily manipulated and observed, frogs provide the unique opportunity to study organ development from the earliest stages. All of these features make Xenopus a premier model for studying the development of the brain, a notoriously complex process that demands an understanding of all stages from fertilization to organogenesis and beyond. Importantly, core processes of brain development are conserved between Xenopus and human, underlining the advantages of this model. This review begins by summarizing discoveries made in amphibians that form the cornerstones of vertebrate neurodevelopmental biology and goes on to discuss recent advances that have catapulted our understanding of brain development in Xenopus and in relation to human development and disease. As we engage in a new era of patient-driven gene discovery, Xenopus offers exceptional potential to uncover conserved biology underlying human brain disorders and move towards rational drug design.

Keywords: amphibian; birth defects; genetics; neural; organogenesis.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to report.

Figures

Figure 1:
Figure 1:. Summary of key techniques used in Xenopus to study brain development.
Several important techniques core to the Xenopus neurodevelopmental biology toolkit are diagrammed here, although the authors note that this figure is not meant to be an exhaustive summary of available technologies, and that these methods are also applicable to the study of other developmental processes. Top panel (A): Summary of advantages of the Xenopus systems and brief overview of central nervous system development. Light blue indicates neural tissues at the embryonic and larval stages shown. Orientations: lateral view with animal pole to the top (oocyte, embryo), lateral view with dorsal to the right (gastrula), dorsal view with anterior to the top (neurula and tadpole), lateral view with anterior to the left (tailbud). Middle panels (B-D): Common techniques used to manipulate Xenopus development, including targeted injection with any of several reagents (B), treatment with pharmacological agents (C), and two examples of explant techniques (D). Note that these methods can be used separately or in combination, as appropriate for the scientific questions of interest. Bottom panels (E-I): Common methods for characterizing typical development or assessing the consequences of experimental manipulations (see B-D) on development. Diagrams depict hypothetical example results based on data from several references; see text for citations. In (E), from left to right: mRNA in situ hybridization shows a reduction in krox20 and hoxb9 expression, a posterior shift in krox20 expression, and no change in otx2 expression on the injected side of a unilaterally manipulated embryo; staining with an antibody against a pan-neural protein shows reduced brain size on the injected side of a unilaterally manipulated embryo; tracing shows axon projections from the right eye to the left tectum; calcium imaging shows increased activity on the injected side of a unilaterally manipulated embryo. (F) shows a heatmap from an omics analysis. (G) shows Western blot results from a co-immunoprecipitation experiment. (H) shows results comparing excitatory post-synaptic current (EPSC) recordings from a control animal (blue) and a manipulated sibling (red). (I) shows sound pulses from an advertisement vocal call.
Figure 2:
Figure 2:. Schematic representations of the developing Xenopus brain.
Lateral views of the Xenopus brain (anterior to the left and dorsal at the top) at NF (Nieuwkoop & Faber) stages 38 (A), 42 (B), 46 (C), and 50 (D). Colors demarcate the developing telencephalon (blue), hypothalamus (purple), diencephalon (green), mesencephalon (pink), midbrain-hindbrain boundary (MHB, grey), and rhombencephalon (yellow). Images are representative of X. laevis and X. tropicalis. See text for anatomical references. Xenopus stages according to Nieuwkoop & Faber, 1994 (Nieuwkoop 1994). Abbreviations: P pallium; SP subpallium; MP medial pallium; DP dorsal pallium; LP lateral pallium; VP ventral pallium; LGE lateral ganglionic eminence; MGE medial ganglionic eminence; a alar; b basal; p prosomere; r rhombomere; Hab habenula; MHB midbrain-hindbrain boundary; OB olfactory bulb.
Figure 3:
Figure 3:. Schematic representations of Xenopus forebrain sections during development
Cross-sectional views of the Xenopus telencephalon (dorsal at the top) at NF stages 38 (A), 42 (B), 46 (C), and 50 (D). Images are representative of X. laevis and X. tropicalis. See text for anatomical references. Xenopus stages according to Nieuwkoop & Faber, 1994 (Nieuwkoop 1994). Abbreviations as in Figure 2, and: V ventricle; VZ ventricular zone; SVZ subventricular zone; MZ marginal zone.
Figure 4:
Figure 4:. Schematic representations of Xenopus stage 38 expression patterns.
Lateral (A, B) and telencephalon cross-sectional (C, D) views showing expression domains of key patterning genes at NF stage 38. Stripes indicate co-expression of genes. See key in figure for color coding. Expression patterns are highly conserved between frogs and mammals (see text for references). Xenopus stage according to Nieuwkoop & Faber, 1994 (Nieuwkoop 1994). Dotted grey line in A indicates sectional plane shown in C and D. Abbreviations as in Figures 2 and 3.
Figure 5:
Figure 5:. Comparison of Xenopus and human brain development after neural tube closure.
Summary of major events in dorsal pallium development over time (B), comparing Xenopus (A) and human (C) development. See key in figure for brain region color coding. Xenopus stages according to Nieuwkoop & Faber, 1994 (Nieuwkoop 1994). Human developmental epochs described as in Sestan & State, 2018 (Sestan and State 2018). Abbreviations: NF Nieuwkoop & Faber, PCW post-conception weeks.
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References

    1. Ablondi Eileen F., Paudel Sudip, Sehdev Morgan, Marken John P., Halleran Andrew D., Rahman Atiqur, Kemper Peter, and Saha Margaret S.. 2020. “Fluorescent Calcium Imaging and Subsequent In Situ Hybridization for Neuronal Precursor Characterization in Xenopus Laevis.” Journal of Visualized Experiments: JoVE, no. 156 (February), 10.3791/60726. - DOI - PubMed
    1. Andino Francisco De Jesús, Jones Letitia, Maggirwar Sanjay B., and Robert Jacques. 2016. “Frog Virus 3 Dissemination in the Brain of Tadpoles, but Not in Adult Xenopus, Involves Blood Brain Barrier Dysfunction.” Scientific Reports, 10.1038/srep22508. - DOI - PMC - PubMed
    1. Andrews Madeline G., and Nowakowski Tomasz J.. 2019. “Human Brain Development through the Lens of Cerebral Organoid Models.” Brain Research 1725 (December): 146470. - PMC - PubMed
    1. An Joon-Yong, Lin Kevin, Zhu Lingxue, Werling Donna M., Dong Shan, Brand Harrison, Wang Harold Z., et al. 2018. “Genome-Wide de Novo Risk Score Implicates Promoter Variation in Autism Spectrum Disorder.” Science 362 (6420). 10.1126/science.aat6576. - DOI - PMC - PubMed
    1. Arendt Detlev, Musser Jacob M., Baker Clare V. H., Bergman Aviv, Cepko Connie, Erwin Douglas H., Pavlicev Mihaela, et al. 2016. “The Origin and Evolution of Cell Types.” Nature Reviews. Genetics 17 (12): 744–57. - PubMed

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