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 In a paper published in Nature Communications, the team, led by
University of Bath mathematical biologist Dr Christian Yates, say
their findings have potential implications for a wide range of
serious embryonic diseases. Piebaldism is one of a series of defects
called Neurocristopathies, some of which manifest themselves as
cancer of the nervous system, deafness, digestive problems and holes
in the heart, which are caused by cells not moving to the right
place as an embryo develops.
Piebaldism is caused by a mutation in a gene called Kit and
manifests itself as regions of fur, hair or skin which lack pigment.
These areas usually arise on the front of an animal - commonly on
the belly and forehead. It's also seen in humans, albeit rarely, in
the form of a white forelock in the hair. Former British government
ministers, and brothers, David and Ed Miliband, both have a white
forelock and might be notable examples of this phenomenon.
Piebaldism is common in cats, because of selective breeding - i.e.
because cat lovers think two-tone felines look nicer.
 "Piebaldism is actually a disease," Yates told Reuters. "It's caused
by cells in the early embryo failing to migrate correctly....failing
to get to the right place. The cells which we're interested in, that
cause piebaldism, are called melanocytes and they're responsible for
pigmentation of hair and of the skin. These cells start at the back
of the embryo and they try to migrate round through the skin and
cover the whole of the (embryo's) skin. When they fail to do that
properly you tend to get regions of skin or hair which are lacking
in pigment, often regions at the front of an animal. This is common
in cats......tuxedo cats, and it's also common in horses and pigs
and even in humans."
Biologists from the University of Edinburgh conducted experiments on
mouse embryos to see how their cells were moving and dividing. On
the basis of their biological hypothesis, Yates's team at Bath
created a mathematical model to confirm that pigment cells migrate
randomly.
Their findings contradict the existing theory that piebald patterns
form because pigment cells move too slowly to reach all parts of the
embryo before it is fully formed.
The team discovered that the process by which these distinctive
pigment patterns form is far more random than originally believed.
"Traditionally people thought that cells didn't make it to the front
of embryos to pigment the belly because they just weren't migrating
fast enough," said Yates. "What we've been able to show through our
studies is that actually, if anything, cells in piebald animals
migrate faster but they're just not proliferating enough. They're
not making enough daughter cells to colonize - or cover - the whole
region of the skin that needs to be covered by the time the
pigmentation pattern is set down."
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Animals acquire the pigmentation patterns on their skin at an early
stage of development and piebaldism occurs when pigment producing
cells migrate incorrectly through the embryo. Darkly colored pigment
cells are unable to spread as far as they do on other, non-piebald,
creatures, in time to pigment the hair and skin.
"What we've been able to tease out from the mathematical model is
it's not necessarily that these cells are migrating in a directed
way," said Yates. "Actually these cells are diffusing, there's no
direction to their migration. It's like when you put a drop of milk
into a cup of coffee that you haven't stirred. Eventually that milk
will be spread evenly throughout your coffee, and these cells are
doing the same sort of thing - they're moving in an undirected
manner and eventually, slowly, they manage to fully colonize the
skin of this animal."
Yates says that the research could further scientific understanding
of a range of serious embryonic diseases called Neurocristopathies,
which are all linked by their reliance on a family of embryonic
cells called neural crest cells.
"By trying to understand piebaldism, which doesn't have a
particularly severe manifestation, so it's just a change in
pigmentation, we can try to use the same techniques that we've
developed to try and model and understand these other more serious
diseases, which effectively are caused by similar mechanisms - cells
not migrating properly in the early embryo," he said.
Yates says his team's mathematical model allows a deeper biological
understanding than would have been possible with experiments alone,
and could potentially reduce the number of animals used in
experiments in this area.
The research was funded by the Medical Research Council, Medical
Research Scotland, the Engineering and Physical Sciences Research
Council and the National Centre for Replacement, Refinement and
Reductions of Animals in Research. It also involved researchers at
the University of Oxford.
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