The Problems with the Gradient of Morphogen Models of Embyrogenesis

gradient

A superb illustration of the morphogen gradient model.

Physiological gradients do exist in embryos. The best known example is the bicoid gradient in Drosophila. Given the discovery of physiological gradients in embryos, it then became common for embryologists and molecular biologists to speak of a “morphogen gradient” across developing tissue that begins at the site of induction, creating a gradient of gene products or “morphogens” across tssue. Morphogens are the basis for the concept of positional information which presumes that a cell can know its position by “reading” the concentration of the molecules of the gradients and then deciding what it is supposed to do, by “looking up” its coordinates in some sort of stored table in its DNA. With these epicycles the problem of embryogenesis was “solved” and, like the far more quantitative Ptolemaic version of the solar system, permeated textbooks and teaching for an extended period of the history of science. Morphogens are still widely taught, along with gene regulatory networks, as if they are a full explanation of embryogenesis.

There are numerous problems with the morphogen gradient model:

  1. In order to maintain a gradient at steady state, besides a steady, spatially defined source for the diffusing molecules, there has to be a sink. This means there must be a way in which diffusing molecules are destroyed or removed along the way and/or at some boundaries. Most people who invoke gradients don’t bother with analyzing and solving the partial differential equations for diffusion of molecules to show how the gradients work. Sinks are rarely, if ever, even considered when the gradient model is invoked.
  2. A common supposition is that the molecules diffuse outside cells instead of through them. This is a convenient assumption, because it permits one to ignore the cellularized structure of space inside an embryo, But even so diffusion must occur in a confined space, if a gradient is to be established. Otherwise the molecules will just diffuse away. If the diffusion is extracellular, then its course is critically dependent on the existence of such confining boundaries. Most of the early development of the axolotl occurs in the outside layer of cells, and is normal whether or not the jelly layers and vitelline membrane are present. So in this case no such confined space exists.
  3. The speed of development may not permit steady state to be reached. This is sometimes considered an advantage in cases where the steady state could not possibly lead to the correct morphology. So we have a steady state invoked except when we don’t want it. In any case, the rate of development varies substantially with temperature over a species’ temperature range for normal development. This would have to be matched to the temperature dependence of diffusion of the molecule which is itself dependent on the temperature variation of the viscosity of the medium.
  4. Ordinary diffusion gradients do not scale well. The consequence for embryos is that for embryos of different sizes there should be widely different proportions of parts but we know that is not the case. There is a limit on the “range” of a morphogen gradient. Such range limits also limit their potential role in growing tissues. Amphibian embryo eggs vary from 0.75 mm to 35 mm, and yet produce adults with substantially the same body plan. As we have a common ancestor with amphibians, our own eggs at 0.07 mm extend the linear size range down by another order of magnitude.
  5. Diffusion gradients follow the superposition principle. This means that a gradient of one substance in, say the x-direction, and a gradient of the same substance in the y-direction, result in a single one-dimensional gradient in the diagonal direction, not a two dimensional gradient. Yet biologists frequently invoke a two dimensional gradient to get the gradient model to fit their data. If you want a two dimensional gradient system you have to have two morphogen gradients with two different sources and sinks placed approximately perpendicular to one another, and three to invoke the third spatial dimension. That’s 6 unidentified sources and sinks.
  6. The fundamental principal of gradients is that cells in high concentrations will respond in one way, while those at low concentrations respond in a different way while those in the middle respond in yet another way. Fluctuations in gradients always occur, especially if the number of diffusing molecules is low. Fluctuations of purported morphogen concentrations make response to particular concentration thresholds problematic.
  7. Each cell has to be able to “read” the morphogen concentration accurately, lest boundaries between tissues become ragged. Gradients are frequently invoked without any explanation how a cell measures a concentration. Yet in embryos boundaries between tissues are generally sharp, at the cellular level.

    Many doubts about the functioning or existence of these so-called “morphogen” gradients have been raised, with alternatives and elaborations, and transport mechanisms other than diffusion being proposed. Like epicycles, multiple, overlapping gradients in the same direction are sometimes required. We won’t review the numerous molecules that have been proposed to be morphogens, but as new biologically active molecules are discovered, they tend to be added to the list and then later sometimes removed. While gradients such as bicoid in Drosophila one-cell embryos are indeed found, the existence of polyembryonic wasps reasonably similar to Drosophila in adult appearance, whose fertilized eggs split into up to 2000 embryos, raises doubts as to the importance of even these intracellular maternal gradients for embryogenesis.

This post contains excerpts from our book Embryogenesis Explained and also from our  article “The organelle of differentiation in embryos: the cell state splitter”, Theoretical Biology and Medical Modelling  (invited review) (Biophysical Models of Cell Behaviour) 2016 in press. We did ask permission to use the gradient model image but they haven’t replied so we hope simply giving them full credit and linking to their website location will do.

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About tumbleweedstumbling

I have three blogs, embryogenesis explained, tumbleweed tumbling AND fulltimetumbleweed. I am a scientist, and my husband and I have written a book which was published by World Scientific Publishing in Nov 2016 called Embryogensis Explained. Full time tumbleweed was my first blog which I worked on during five years of living full time in a travel trailer. I have now retired that blog in favour of Tumbleweeds Tumbling since we bought a stick house in April 2015 and are no longer full-time. I have a blended family of five sons and one daughter, all grown up now. I am (step)grandmother to nine boys and one girl. My husband and I have two dogs and a cat. We spend summers in Manitoba, Canada, in a 480 square foot house on a half acre of land in the tiny town of Alonsa. We spend winters in the USA. My husband is retired and being a US citizen, he does volunteer work in winters for Gulf Specimen Marine Lab in Panacea Florida as their emeritus. I retired in Sept 2013 and so far I am loving it.

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