March 7, 2007

Embryology Biology 441 Spring 2007 Albert Harris


Embryological Mechanisms

As we already know

Anatomy consists mostly of certain geometric arrangements of differentiated cells.

(Extracellular matrix proteins like collagen also has to get put at the right places; and so does cartilage, and bone.

Embryology is the study of causal mechanisms by which genes cause these geometric arrangement of cells & matrix.

Combinations of different kinds of mechanisms occur:
(and embryologists disagree about which kind of mechanism causes each specific part of our anatomy.)

Three main kinds of theories:

1) Linear gradients, to which each cell responds to certain combinations of chemical concentrations. Segmental or other repeated structures are claimed to be caused each by a different combination of chemical signals ("morphogens")
(This idea is called "Positional Information")
[Molecular geneticists very much WANT embryos to work this way because it reduces all problems to finding signal molecules & receptors; Such gradients were discovered in Drosophila, & won a Nobel Prize!]

2) Chemical Pre-Patterns, in which differentiation is controlled by complex spatial patterns of high and low concentrations of signals (also called "morphogens")

Alan Turing's "Reaction-Diffusion Systems" are hypothetical mechanisms that could generate pre-patterns;
But could also generate simpler gradients.
No example has been proven FOR SURE in embryos.

Liesegang rings are a non-living reaction diffusion system,
Using only 2 chemicals (3 if you count the gel)
For which NOBODY has ever discovered the true cause. (But we do know FOR SURE that it works in the lab.)

Lessons to be learned from Liesegang rings.

    a) People have a big blind spot for self-organization.
    b) Reaction-diffusion can produce regular patterns.
    c) Many alternative mechanisms could make patterns.
(Including disproved explanations for Liesegang rings!)

A German scientist (Hans Meinhardt) has published books with many examples of actual animal color patterns that can be generated by reaction diffusion systems.

3) A different kind of theory (or is it a special case of #2?):
mechanical forces directly create anatomical patterns.

The scientist most responsible for this idea was D'Arcy Thompson, who was a professor in Scotland, and wrote a famous book "On Growth and Form".

The scientists who came closest to proving actual examples were David Stopak (a graduate student in this department) and me. We showed that crawling cells exert "traction" forces that are strong enough to rearrange collagen, and that collagen injected into limb buds gets rearranged.

Other scientists have subsequently reported similar results and proposed they explain formation of various organs.

Biographical interviews on these issues were published last year in a Spanish journal, (International Review of Developmental Biology) with lots of illustrations.
Int. J. Dev. Biol. Vol 50 pages 103-111 (2006), pdf link
Int. J. Dev. Biol. Vol 50 pages 93-101 (2006), pdf link

These interviews are not required reading, but you might find them interesting.


The textbook explanation for limb development is now that
The anterior-posterior axis of limb asymmetry is controlled by gradients of the "Sonic Hedgehog" protein, with its highest concentration on the rear side of each limb bud;

and that the dorso-ventral axis of limb asymmetry is controlled specifically by ectodermal cells and by expression of the Wnt-7a gene (more in the dorsal cells);

and that the medio-lateral axis is controlled by fibroblast growth factor produced in the apical ectodermal ridge.

The mechanical causes of shapes are generally assumed to be causally "down-stream" and therefore not important.

No textbook even wonders why the AER is a special shape, nor relates its shape to differences in tension & curvature.

Future scientists, of the age of students in this course, have lots of important questions left for them to solve.

A few specific questions:

i) Can cell differentiation sometimes be controlled by how strongly a cell is compressed or stretched?

ii) Why is the Apical Ectodermal Ridge a special shape?
(Because its cells have a special pattern of contractility?
Because special patterns of forces are imposed on it?)

iii) Why use movements to control cell differentiation?
(gastrulation, neurulation, somite formation, etc.)

iv) Why do some cell types (skeletal muscles, pigment cells, primordial germ cells) begin cell differentiation at one place, but then actively crawl somewhere else?

None of these would be expected from assuming that each cell type differentiates according to chemical gradients.

Future embryologists may look back on our times as having been dominated by a chemical version of preformationism.

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