Notch is Required for Neural Progenitor Proliferation During Embryonic Eye Regrowth
Posted on: 10 March 2024 , updated on: 12 March 2024
Preprint posted on 2 February 2024
The role of a conserved cell signaling pathway in regulating the proliferation of neural progenitors during embryonic eye regrowth in a frog.
Selected by Mina Basily
Categories: cell biology, developmental biology
Introduction:
The Notch pathway is a conserved cell signaling system in most metazoans, playing a quintessential role in development and regeneration. Notch is a cell surface receptor that interacts with membrane-bound ligands on neighboring cells, regulating cell fate, differentiation, proliferation, and apoptosis pathways [1, 2].
In this preprint, the authors explore the significance of Notch signaling, and specifically Notch1 signaling, in embryonic eye regrowth and its role in inducing retinal progenitor cell proliferation in response to injury.
Major findings:
The role of Notch signaling in regrowing a full-size embryonic eye
To investigate the possible role of Notch1 in Xenopus embryonic eye regrowth, the authors chemically inhibited Notch signaling after an eye ablation procedure. The chemical inhibition of Notch signaling was achieved by MG132 and DAPT treatment, and this inhibition remarkably reduced the size of the regrown embryonic eye compared with the control.
To avoid any overlap in the results, and to make sure that their observations were due to the lack of Notch signaling, the authors resorted to a molecular approach to inhibit Notch signaling; they used two fluorescein morpholinos one of which is a verified morpholino against Xenopus Notch1 mRNA, and the other is a control morpholino. Each of the two morpholinos (MO) was injected separately into the left dorsal blastomere of four-cell embryos at a concentration that does not affect embryogenesis. The Notch1 morpholino reduced the size of the regrown embryonic eye in a way that resembled the effect of the chemical inhibition approach used earlier.
To confirm that the Notch1 morpholino results were due to the absence of Notch1, the preprint authors co-injected dexamethasone-inducible Notch intracellular domain (NICD) mRNA (NICD is an active form of Notch) along with the Notch1 morpholino into four-cell embryos. After eye ablation, they then injected dexamethasone to induce the activity of NICD in the presence of Notch1 morpholino; this restored full eye regrowth rates to control levels.
Revealing a critical time-window for Notch signaling during the eye regrowth
The authors’ previous experiments revealed that 87% of eye size was restored within the first two days of regrowth, which led them to suggest that maybe Notch signaling is required the most during this initial regrowth period. To investigate this hypothesis, they exposed the embryos to an MG132 inhibitor after an eye ablation at different time points within five days after the surgery. They found that the inhibition of Notch signaling during the first day (day 0) alone matched the effect of exposure to the inhibitor for five consecutive days (day 0–5), and any attempt to use the inhibitor after passing the first 24 hours post-surgery failed and the size of the regrown eye wasn’t affected (Figure 1).
Figure 1: (A) The study compares regrown eyes after MG132 treatment for various durations from surgery, (B) Graphical representation of percent of the population achieving full regrowth at 5 dps, * = p<0.01.
The role of Notch signaling in retinal differentiation and proliferation
To investigate the effect of Notch signaling on cell differentiation, three groups of embryos were fixed 3 days post-surgery: one was exposed to MG123, one was injected with Notch1 morpholinos, and one was the control. All the three groups were stained with an anti-Islet1 antibody as a marker of ganglion cells and an anti-Rhodopsin antibody as a marker of rod photoreceptor cells, one at a time. The three groups showed similar retinal patterns in terms of morphology and cell positioning with size. This means that Notch inhibition doesn’t affect retinal differentiation. To investigate the effect of Notch inhibition on cell proliferation, embryos were treated with MG123 or Notch1 morpholinos. This was followed by eye ablation surgery, after which the embryos were fixed, sectioned, and stained with (H3P) antibody, a mitosis marker. The results showed a dramatic decrease in H3P within Notch-inhibited cells compared with the control, which indicates the important role of Notch in cell proliferation.
Overexpression of Notch1 restores the ability of embryonic eye regrowth during V-ATPase inhibition
The inhibition of Notch resembled the phenotypes observed when the proton pump V-ATPase is inhibited. This proton pump is considered an important player in allowing eye regrowth but not development, which is why the authors wanted to investigate if Notch and V-ATPase could interact to regulate eye regrowth. To investigate this, they injected four-cell embryos with Dex-inducible NICD mRNA along with Concanamycin A,a V-ATPase inhibitor, after eye ablation. Another control group was treated with Concanamycin alone. The first group was able to regrow eyes in 75.5% of cases, whereas the control group was only able to regrow eyes in 22.6% of cases. This highlights the importance of the ectopic activation of Notch in rescuing eye growth and the fact that it acts downstream ofV-ATPase.
Why I chose this preprint and what I liked about it:
This preprint describes a novel role for Notch signaling during eye regrowth. Understanding the different aspects that govern regrowth and regeneration in animals such as Xenopus will contribute to solving the complex riddles faced when studying regeneration in higher vertebrates. Also, this study allows us to better appreciate how important Notch signaling is in processes such as proliferation and neural regrowth. I particularly liked how the authors have used different inhibitory approaches to confirm the role of Notch, and how they managed to describe the relationship between Notch and V-ATPase in allowing eye regrowth.
Questions for the authors:
- Do you have any idea if Notch inhibition affects Pax6 in any way during the regrowth?
- Would you consider, in the future, any molecular study to compare the role of Notch in regulating cell proliferation and differentiation between eye regrowth and eye development?
- What is the future of this project?
References:
- Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. 2013 May 15;126(Pt 10):2135-40. doi: 10.1242/jcs.127308. Epub 2013 May 31. PMID: 23729744; PMCID: PMC3672934.
- Gao J, Fan L, Zhao L, Su Y. The interaction of Notch and Wnt signaling pathways in vertebrate regeneration. Cell Regen. 2021 Apr 1;10(1):11. doi: 10.1186/s13619-020-00072-2. PMID: 33791915; PMCID: PMC8012441.
doi: https://doi.org/10.1242/prelights.36762
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