Researchers explore link between human birth defect syndrome, cancer metastasis

February 3, 2010

Some cells are natural rule-breakers. Neural crest cells for example, not only migrate throughout the body during development (most cells are more selective in their wandering), they are also more developmentally flexible than their predecessors (a no-no for nearly all cell types). Now researchers at the Stanford University School of Medicine have shown that a protein that controls DNA accessibility is responsible for the cells' unruly ways.

The finding not only offers a better understanding of the molecular basis of a spontaneous genetic disease in humans called CHARGE syndrome, it may also be important in understanding how gain the ability to migrate, or metastasize.

"Most cells lose developmental potential as they differentiate," said Joanna Wysocka, PhD, assistant professor of developmental biology and of chemical and . "But neural crest cells are a spectacular example of migratory cells that are capable of becoming over 100 different cell types, including neurons, the bone and cartilage of the face, jaw and teeth, pigment cells and certain heart structures." Wysocka is the senior author of the research, which will be published online Feb. 3 in Nature.

Wysocka, who studies how chromatin modification affects development, became interested in the cells when it became apparent that mutations in a protein called CHD7 were responsible for CHARGE syndrome. The condition's name is an acronym for a constellation of associated birth defects that affect about one in 10,000 children. Children with the disorder have a combination of craniofacial malformations; eye, ear and ; and other abnormalities. The unusual combination of this wide array of symptoms led physicians and researchers to speculate that the problem arose early in development in the neural crest cells.

Most DNA in a cell is tightly wrapped around proteins and compacted into what is called chromatin. CHD7 belongs to a class of proteins called ATP-dependent chromatin remodelers, which orchestrate the movement of the DNA packing proteins to provide or restrict access to particular genes. Choosing which portions of DNA to expose and which to keep tightly bundled can control cell fate.

"This was fascinating to me because next to nothing is known about chromatin regulation in neural crest cells, which are multipotent by nature," said Wysocka, who is also a member of Stanford's Cancer Center. "And yet, CHD7's involvement in CHARGE indicated that this chromatin remodeler is a critical component of the proper migration and specialization of the neural crest."

The neural crest forms early in development (in humans, at three to five weeks of gestation) when a portion of the cells that will become the embryo folds inward into a tube that will become the brain and the spinal cord. Neural crest cells form at the seam of this tube and rapidly migrate throughout the body to form the bones and of the face; the neurons and glia of the peripheral nervous system; heart structures; a portion of the gut; and many other important components of the developing organism.

Ruchi Bajpai, PhD, a postdoctoral scholar in Wysocka's lab and first author of the study, coaxed human embryonic stem cells to become what resembles functional neural crest cells in a laboratory dish. These cells could become neurons and many other cell types derived from the neural crest. When the researchers suppressed CHD7 expression, they saw that fewer neural crest cells formed and migrated across the surface of the dish.

For obvious ethical reasons, the researchers couldn't study the effect of tweaking CHD7 levels in human embryos. Because the problems occur so early in development, Wysocka and her colleagues turned to frog embryos to test how CHD7's activity affected neural crest cells in a living animal. Unlike mice, frog embryos develop outside of the body and can be easily monitored. Researchers found that blocking CHD7 expression or its activity in frog embryos interfered with the ability of the neural crest cells to migrate during development. What's more, the resultant tadpoles also exhibited many of the major clinical features of human CHARGE syndrome.

"This gave us confidence that we were on the right track," said Wysocka. "It's apparent that CHD7 is required for the reprogramming and migration of the neural crest cells, which is when one would predict major changes in chromatin organization would be taking place."

Further research showed that CHD7 works with another protein called PBAF to bind areas of DNA associated with, but far from, genes involved in neural crest cell specialization and migration. These so-called distal DNA elements control the expression of faraway genes. "It's a long-distance relationship," said Wysocka.

The finding may not only lead to a new understanding of CHD7's role in CHARGE syndrome, it also suggests that CHD7 and PBAF may be involved in the reprogramming and migration of other types of cells, such as cancer cells. Two genes controlled by CHD7 and PBAF — called Twist and Slug — have been implicated in metastasis in many human cancers.

"If we can cause a CHARGE syndrome in tadpoles simply by reducing CHD7 levels by twofold," said Wysocka, "it's possible that increases in CHD7 levels in cancer may significantly enhance the metastasis program. Interestingly, CHD7 duplications have been recently associated with small-cell lung cancer, one of the most highly metastatic and aggressive types of cancer. "

Explore further: How do cells travel through our bodies?

Related Stories

How do cells travel through our bodies?

January 25, 2005

One of the most basic yet least understood processes in our bodies is how cells crawl along tissues. This behavior is essential to the formation of an embryo and other processes, but it must be tightly controlled. A disturbance ...

Merkel cell originates from skin, not the neural crest: study

October 2, 2009

Case Western Reserve University School of Medicine assistant professor of pediatrics, neurosciences and otolaryngology, Stephen M. Maricich, M.D., Ph.D., and his team found that Merkel cells originate in the skin, not the ...

Recommended for you

How the finch changes its tune

August 3, 2015

Like top musicians, songbirds train from a young age to weed out errors and trim variability from their songs, ultimately becoming consistent and reliable performers. But as with human musicians, even the best are not machines. ...

Cow embryos reveal new type of chromosome chimera

May 27, 2016

I've often wondered what happens between the time an egg is fertilized and the time the ball of cells that it becomes nestles into the uterine lining. It's a period that we know very little about, a black box of developmental ...

Shaving time to test antidotes for nerve agents

February 29, 2016

Imagine you wanted to know how much energy it took to bike up a mountain, but couldn't finish the ride to the peak yourself. So, to get the total energy required, you and a team of friends strap energy meters to your bikes ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.