Findings: The mighty cadherin

Cells are interesting. There are hundreds of cell types, including cardiac cells, epithelial cells, red blood cells, and neural cells. Cells of a particular kind tend to grow together. Cardiac precursor cells proliferate into the heart. Neural crest cells in the spinal cord give rise to the neurons and cerebral cortex. Muscle fibers are formed by the fusion of myoblast cells.

On the inside, cells get more interesting.

Cells communicate with each other. Sometimes they direct the development of their neighbors by releasing signals that trigger cell-signaling pathways in recipient cells. Cells have an active architecture. They are held up by a vaulted scaffolding called the cytoskeleton, and are home to mine carts (dynein and kinesin) that travel up and down the cell using a network of rails, called the microtubules.

Cells engulf and destroy harmful cells (macrophages), produce antibodies (B-cells), and direct the regulation and expression of their own genomes.

This work of cells is quite a remarkable feat. If enough cells are put together, they can build a highly developed, multicellular organism that eats, thinks, and breathes. But without a means to hold them together, their work is futile, and a person would dissociate into a pool of cells before even being born.

The job of holding this network of trillions of cells together is left to the cadherin molecules. Cadherins can be thought of as the strings of a marionette puppet. Without them, the arms and legs of a human being would fall to the floor.

The cadherin molecule is a single protein chain that extends from the surface of one cell and attaches to the cadherin molecule on nearby cell. Cadherin molecules are specific, allowing cardiac cells to stick to cardiac cells, and muscle cells to stick to muscle cells. For this reason, there are many subclasses of cadherins. E-, N-, and P-cadherins are found in epidermal, neural, and placental cells, respectively.

The activity of cadherins is evident very early in development.

A mutation in the mouse E-cadherin gene results in a mouse embryo that completely dissociates at the morula stage (when the baby mouse is merely an amalgamation of 16 to 32 cells). Injecting extra N-cadherin into a two-cell frog embryo results in abnormal tissue formation. The tissues of the frog embryo clump, fuse, and thicken in abnormal places, revealing that cadherin is not only required, but required in specific amounts.

This brings us to an important historical puzzle about cadherins, recently expounded upon (and resolved) in the February 2008 issue of Science magazine. If the function of cadherins is so important to an organism’s development, it is perplexing that cadherin genes are absent from all microorganisms and almost all single-celled organisms.

Let us take a step backwards to see what this means. Metazoans are members of the animal kingdom. They are always multicellular. Metazoans include tigers, jellyfish, elephants, and chickadees. Nonmetazoan multicellular organisms are microorganisms that are not animals. These would include plants, fungi, and algae. Nonmetazoan multicellular organisms also include microscopic organisms like E. coli, amoeboids, and the ocean-dwelling crenarchaeota.

The widely held theory of evolution implies that multicellular organisms, like metazoans, evolved from the joining and recombining of single-celled ancestors, like nonmetazoans. But for this to happen, cells must first stick together. Sticking together involves adhesion molecules, like cadherin.

But in our unicellular ancestors, cadherins are strangely missing.

In their article, University of California at Berkeley researchers Monika Abedin and Nicole King took this issue to task. They sequenced the genome of a choanoflagellate (a single-celled organism with a flagella, or whip-like propeller) called Monosiga brevicollis and compared the number of cadherin genes in the microorganism with the number of cadherin genes in four metazoans — the sea anemone, the fruit fly, the sea squirt, and the house mouse.

The numbers are similar: 23 cadherins per genome for M. brevicollis, compared to 46, 17, 32, and 127 for the sea anemone, the fruit fly, the sea squirt, and the house mouse. This is a remarkable piece of news. It is also strange, because choanoflagelletes are typically unicellular and do not form cell-to-cell contacts.

This finding also humbly suggests that M. brevicollis could be the unicellular ancestor to animals and our closest living microscopic relatives. And it all begins and ends with cadherins. The cadherin molecule keeps multicellular organisms from disintegrating. But it is also an important molecule for studying animal evolution.

Cadherins are also mediators of cancer — when cadherins fail, cells slip off a tumor and metastasize, spreading the cancer throughout the body.

It is time to recognize these hardworking heroes of organismal biology. When you feel like you are falling apart, is it the cadherin that is keeping you together.