How the cat got its spots

(Reuters) - A team of biologists and mathematicians from three British universities are challenging conventional thinking on piebaldism - a benign genetic disease caused by a mutation which results in the distinctively colored fur patches of cats, horses, pigs, dogs, and deer, while human hair is occasionally affected.

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.”

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.