A Scube2-Shh feedback loop links morphogen release to morphogen signaling to enable scale invariant patterning of the ventral neural tube

Summary:

How do morphogen gradients adapt to size differences? Within populations, individuals vary in size, yet their proportions are similar. This process is known as scale-invariant patterning, and it is a crucial process in development [1,2]. A well-characterized example of this mechanism is the patterning of the neural tube, where it has been shown that embryonic proportions are constant in mouse embryos of different sizes, as well as in embryos of different species. In this preprint, Collins et al. investigate the mechanism by which sonic hedgehog (Shh) morphogen gradient scales in the ventral neural tube in zebrafish embryos of different sizes.

To generate embryos of varying sizes, they surgically remove some cells in the blastula stage (prior to neuroectoderm formation); this rendered embryos of smaller sizes but with constant proportions. Quantifications of a Shh target demonstrate that the response is scaled following embryo reduction.

The authors focus their attention on Scube2, a lipid-binding protein required for Shh release non-cell-autonomously, which is expressed in the dorsal and intermediate neural tube. They demonstrate that Scube2 is a diffusible factor distributed throughout the embryo that is secreted from dorsal cells, and it is repressed by Shh signaling.

The authors next wanted to test whether Scube2 expression would scale like Shh reporter genes in sized-reduced embryos. When they measure Scube2 expression in size-reduced embryos, they find that the reduction in Scube2 levels is not scaled: the levels are 50% reduced at DV positions of maximal expression compared to controls, a pattern not found for al scaling invariant genes formerly tested. In addition, when Scube2 is overexpressed in size-reduced embryos, Shh target response is of the same amplitude in embryos of all sizes. This implicates that control of scube2 is responsible for adjusting the Shh signalling gradient in a decreased tissue.

 

Why I chose the paper:

 Embryo development is strikingly robust, and it can cope with variations in size or morphological alterations [3], however the mechanisms that allow embryos to adapt are poorly understood. Collins et al. identify a size-dependent factor that allows the scaling of Shh morphogen gradient in embryos of reduced sizes, adjusting proportionally to the embryonic axis.

The first thing I liked about this work is the surgical method developed in The Megason group to change embryo size and look at size-dependent scaling. They generate perfectly viable and scaled embryos by removing a big percentage of cells at the blastula stage without the need of genetically altering the embryos, which then allows them to perturb different genes.

Their molecular characterization with fish mutants and transgenic reporters is reminiscent of an expander-repressor model [1]. In this model, the morphogen inhibits the expression of an “expander” molecule (Scube2 ), which functions to increase the gradient, holding back morphogen levels at a specific position. What I like about this model is that it does not rely on morphogen diffusion or degradation – that are common molecular properties of proteins regardless of the embryo size – but it relies on the feedback between “expander” and “inhibitor” to continuously adjust the gradient globally. It will be good to see how an expander-repressor model adjusts to their findings and what new predictions we can infer from the model.

Further reading:

Almuedo-Castillo, M., Bläßle, A., Mörsdorf, D., Marcon, L., Soh, G. H., Rogers, K. W., … Müller, P. (2018). Scale-invariant patterning by size-dependent inhibition of Nodal signalling. Nature Cell Biology, 20(9), 1032–1042. http://doi.org/10.1038/s41556-018-0155-7

Ben-Zvi, D., & Barkai, N. (2010). Scaling of morphogen gradients by an expansion-repression integral feedback control. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 6924–9. http://doi.org/10.1073/pnas.0912734107

Umulis, D. M., & Othmer, H. G. (2013). Mechanisms of scaling in pattern formation. Development (Cambridge, England), 140(24), 4830–43. http://doi.org/10.1242/dev.10051                                         

Questions to the authors:

1. The neural tube is highly similar in fish and mammals even though there are some differences in the formation of the neural tube. Do the authors think that the expander-repressor model through Scube2 will operate similarly in mammals?
2. The size reduction of the embryos occurs early in development, before any Shh has been secreted. Do the authors think their identified mechanism can operate after injury, once the morphogen gradient is ongoing?
3. Invariant scaling achieves the same proportions of embryos that vary in size. Do the authors know if the scaling mechanisms have the same tempo in embryos of different sizes?

References:

1. Shilo, B.-Z., & Barkai, N. (2017). Developmental Cell Perspective Buffering Global Variability of Morphogen Gradients. Developmental Cell, 40, 429–438. http://doi.org/10.1016/j.devcel.2016.12.012.
2. Garric, L., & Bakkers, J. (2018). Shaping up with morphogen gradients. Nature Cell Biology, 20(9), 998–999. http://doi.org/10.1038/s41556-018-0168-2.
3. Lawrence, P. A., & Levine, M. (2006). Mosaic and regulative development: two faces of one coin. Current Biology, 16(7), R236–R239. http://doi.org/10.1016/j.cub.2006.03.016.

Tags: morphogen gradient, neural tube, sonic hedgehog, zebrafish

doi: https://doi.org/10.1242/prelights.5954

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