XB-ART-53024Genesis. January 1, 2017; 55 (1-2):
What we can learn from a tadpole about ciliopathies and airway diseases: Using systems biology in Xenopus to study cilia and mucociliary epithelia.
Over the past years, the Xenopus embryo has emerged as an incredibly useful model organism for studying the formation and function of cilia and ciliated epithelia in vivo. This has led to a variety of findings elucidating the molecular mechanisms of ciliated cell specification, basal body biogenesis, cilia assembly, and ciliary motility. These findings also revealed the deep functional conservation of signaling, transcriptional, post-transcriptional, and protein networks employed in the formation and function of vertebrate ciliated cells. Therefore, Xenopus research can contribute crucial insights not only into developmental and cell biology, but also into the molecular mechanisms underlying cilia related diseases (ciliopathies) as well as diseases affecting the ciliated epithelium of the respiratory tract in humans (e.g., chronic lung diseases). Additionally, systems biology approaches including transcriptomics, genomics, and proteomics have been rapidly adapted for use in Xenopus, and broaden the applications for current and future translational biomedical research. This review aims to present the advantages of using Xenopus for cilia research, highlight some of the evolutionarily conserved key concepts and mechanisms of ciliated cell biology that were elucidated using the Xenopus model, and describe the potential for Xenopus research to address unresolved questions regarding the molecular mechanisms of ciliopathies and airway diseases.
PubMed ID: 28095645
PMC ID: PMC5276738
Article link: Genesis.
Grant support: K99 HL127275 NHLBI NIH HHS
Genes referenced: bmp4 ccp110 cetn4 e2f4 e2f5 foxa1 foxj1 foxj1.2 foxn4 gmnc mab21l1 myb nkx2-2 notch1 pax6 pitx2 rfx2 rfx3 tfdp1 tp73 tuba4b wnt1
Article Images: [+] show captions
|Figure 1. Ciliated tissues in Xenopus laevis embryos and tadpoles. Immunofluorescent staining of Xenopus laevis embryos with anti-acetylated-α-tubulin antibody to reveal cilia (green) of (A) the gastrocoel roof plate (GRP) at stage 17, (B) the neural tube at stage 26, and (C) the embryonic mucociliary epidermis at stage 32. The different types of ciliated cells are shown in magnified views. Co-staining: Phalloidin for F-actin (red), anti-serotonin for small secretory cells (5HT; blue). Basal bodies were visualized by expression of centrin4-rfp (red) and gfp-cp110 (blue). Digitized images and developmental data from Nieuwkoop and Faber (1994) Normal Table of Xenopus laevis (Daudin) were obtained from Xenbase.org|
|Figure 2. Transcriptional and post-transcriptional regulation of multi-ciliated cells. (A) Transcriptional control of core MCC gene expression in multi-ciliated cells. Arrows = activation, T = inhibition, solid line = major contribution, dotted line = supporting contribution. (B) A transcriptional/post-transcriptional regulatory module titrates levels of Cp110 to allow for ciliogenesis in MCCs. Left panel: cp110, miR-34b/c, and miR-449a-c are directly regulated by ciliary transcription factors (color code is the same as in A). Right panel: optimal (intermediate) Cp110 levels are required for ciliogenesis. Summary of effects of too much or too little Cp110 on MCC cilia formation|
|Figure 3. Signaling regulation in the Xenopus mucociliary epidermis. Overview of signaling regulation and development of the mucociliary epidermis. (A) Developmental processes over the time-course of mucociliary epithelium formation. Corresponding stages of Xenopus development are depicted on the left. Digitized images and developmental data from Nieuwkoop and Faber (1994) Normal Table of Xenopus laevis (Daudin) were obtained from Xenbase.org. (B) Schematic summary of signaling events and key transcription factors regulating mucociliary cell fate specification. Binary decisions based on high versus low level input from signaling events are shown as triangle representing two sides of a signaling gradient (for BMP, Wnt and Notch). Additional contributions from signaling pathways are depicted as, for example, “+Wnt.” In later stages, BMP signaling (yellow) is also required for intercalation of all cell types derived from subepithelial progenitors|