08/05/2004 07:00:00

Fish, Frog, and Fly Share a Molecular Mechanism to Control Embryonic Growth

PASADENA, Calif. — Oriented cell division is a fundamental process in developing organisms, whether you are a worm, a fruit fly--or a human. As an embryo begins to grow, cells divide again and again, from the single fertilized egg to the countless cells present at birth. These cell divisions are not haphazard; instead, they are often precisely oriented, playing an important role in building an embryo of the right size and shape, and with the right body "parts"--the control of cell division also plays a central role in placing cells in the proper positions to build organs that will contain the correct cell types.

The orientation of cell divisions has been well studied in invertebrates, especially in Caenorhabditis elegans (worm) and Drosophila melanogaster (fruit fly), but relatively little has been known about oriented cell division in vertebrates. Now for the first time, researchers at the California Institute of Technology report that the molecular machinery that underlies oriented cell division in invertebrates serves a similar but twofold purpose in the development of the vertebrate embryo. For one, it is responsible for orienting cell division, or mitosis. For another, it's responsibile for the movements that elongate the round egg into the vertebrate body plan; that is, the shape of the particular animal. The research appears in the August 5 edition of the journal Nature (http://www.nature.com/).

The researchers are recent graduates Ying Gong '04 and Chunhui Mo '03, working with Scott Fraser, the Anna L. Rosen Professor of Biology and director of the Biological Imaging Center. Using the zebrafish, a card-carrying vertebrate, as their animal model, the researchers first marked certain cells with fluorescent proteins. Then, using a four-dimensional confocal microscope, they were able to follow the motions of these cells in real time, as the body plan of the zebrafish took shape during development, or gastrulation. The researchers found that cells in dorsal tissue divide in an oriented fashion, with one of the two daughter cells from each division moving towards the head, and the other towards the future tail. They were able to determine that such oriented cell division is a major driving force for the extension of the body axis--the growth of the embryo into the animal's final shape.

By combining their advanced imaging tools with molecular biological techniques, the researchers were able to show that the driving force for these oriented divisions is the Wnt "pathway," a ubiquitous cascade of specific proteins that trigger cellular function. Research over the past decade has shown that the Wnt pathway controls the patterns, fates, and movements of cells in both vertebrates and invertebrates. One major branch of this biochemical communication network is the planar cell polarity (PCP) pathway. In previous work from the Fraser lab and their collaborators, the PCP pathway has been shown to guide the tissue motions that convert the spherical frog embryo into the familiar shape of the elongated tadpole. This is a key process in the life of the frog, termed convergent extension. Each cell attempts to "elbow between" the row of cells to its left or its right. "This simple motion has a profound effect on the length and width of the embryo," says Fraser; "think of a band marching shoulder to shoulder on a football field. If half of the rows of marchers merged with the adjacent row, the band would be half as wide and twice as long."

The trio of researchers explored the effects in fish embryos of altering the many proteins in the Wnt-PCP signaling pathway, including some of the potential signals and co-receptors (proteins called Silberblick/Wnt11, Dishevelled, and Strabismus). They were expecting to see an alteration in the convergent-extension motions. Instead, what they found was a major alteration in the orientation of cell division. When they blocked the Wnt pathway, cell division did not take place along the head-tail axis, but randomly. In normal fish embryos, the oriented divisions lengthened the body axis by nearly twofold. With randomization, though, a short and squat embryo was created.

Given that the same PCP pathway is involved in controlling cell division in the invertebrates, C. elegans and D. melanogaster, and the vertebrate zebrafish, the results suggest that the pathway has an evolutionary conserved role. That is, that across a wide variety of animal species, such pathways share a common function, perhaps reflecting a common origin in the biological past.

"The amazing thing about these studies is that they show that the many varied mechanisms that can create the long and narrow body plan of a fish, frog, or fly come under a common molecular control mechanism," Fraser says. "Work in frog embryos from John Wallingford (formerly of UC Berkeley, currently at University of Texas, Austin) and Richard Harland (UC Berkeley) have established a link between these motions and neural tube defects (such as craniorachischisis and spina bifida). Our new experiments have already prompted a new round of collaborative experiments to determine if the same molecular pathway controls convergent extension, cell division, or both in mammals. The answers to these questions promise new insights into the underlying cause for some of the devastating birth defects seen in humans. "

MEDIA CONTACT: Mark Wheeler (626) 395-8733 wheel@caltech.edu

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Written by Marcus Woo