New York University biologists have discovered new mechanisms
that control how proteins are expressed in different regions of embryos, while
also shedding additional insight into how physical traits are arranged in body
plans. Their findings, which appear in Cell,
call for reconsideration of a decades-old biological theory.
The researchers investigated a
specific theory—morphogen theory, which posits that proteins controlling traits
are arranged as gradients, with different amounts of proteins activating genes
to create specified physical features. This theory was first put forth in the
1950s by mathematician and World War II code breaker Alan Turing and refined in
the 1960s by Lewis Wolpert. It has been used to explain why a tiger has
stripes, among other phenomena.
But some biologists have raised
questions about the theory, which contends that physical features are
necessarily tied to absolute concentrations of proteins within the morphogen
gradient. If a certain critical mass of protein is present, then a given
physical feature—for example, cells that make the skin on your forehead—will
appear. If less than that critical mass is present, a different structure—say,
the skin that makes your eyebrows—will appear, and a boundary will be formed
between the two structures.
But alternative views have
suggested that physical features are not necessarily the result of a specified
number of proteins, but, rather, come from more complex interactions between
multiple gradients that work against one another.
The NYU biologists explored this
process by studying the fruit fly Drosophila,
a powerful model for studying genetic development as it is amenable to precise
genetic manipulations. They focused on one protein, Bicoid (Bcd), which is
expressed in a gradient with highest levels at the end of the embryo that will
become the mature fly’s head.
The researchers, headed by
Stephen Small, chair of NYU’s Department of Biology, examined a large number of
target genes that are directly activated by Bcd. Each target gene is expressed
in a region of the embryo with a boundary that corresponds to a specific
By examining DNA sequences
associated with these target genes, the NYU researchers discovered binding
sites for three other proteins—Runt, Capicua, and Kruppel—which all act as
repressors. All three proteins are expressed in gradients with highest levels
in the middle part of the embryo, and thus are positioned in exactly the
opposite orientation compared to the Bcd activation gradient.
By changing the spatial
distribution of the repressors and by manipulating their binding sites, Small
and his colleagues showed that these repressors antagonize Bcd-dependent
activation and are absolutely critical for establishing the correct order of boundaries
that are found in a normal embryo.
In other words, contrary to
Turing’s theory, a single gradient of proteins does not have sufficient power
to form the same body plan in each member of a species; however, if there are
multiple gradients that work against each other, then the system becomes robust
enough for normal development.
While the results raise questions
about morphogen theory, the researchers explained that their findings did not “falsify” it, but, rather, suggested it needed some additional refinement.