December 19, 2003

Cell connections critical to organ formation

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Peter A. Kolodziej, Ph.D

Cell connections critical to organ formation

Like a child building with interlocking blocks, the developing organism connects cells to form complex tissues and organs. Vanderbilt University Medical Center researchers have discovered another molecular feature of the process that “glues” cells together.

The findings, reported in the Dec. 15 issue of Development, offer insight to tissue development and remodeling. The research focuses on the molecular players that work together to form adherens junctions – spots of cell-cell connection.

“How you make these adherens junctions is critical for making tissues,” said Peter A. Kolodziej, Ph.D., assistant professor of Cell & Developmental Biology. “Defects in the assembly of these cellular junctions may underlie many different diseases of skin and other organs.”

It is known, Kolodziej said, that mutations in one member of the junctions — a protein called E-cadherin – can transform a normal cell into a metastatic tumor cell. About 95 percent of human cancers arise from epithelial cell types that rely on E-cadherin adhesion to maintain their orderly structure. Without this molecular “glue,” cancer cells are able to metastasize.

E-cadherin is more than just glue holding cells together though. Inside the cell, it helps organize the cytoskeleton – the cell’s supporting framework – by interacting with other proteins.

“Although it’s known that controlling junctions and their assembly is really important for tissue integrity and remodeling, it’s not quite understood what all the molecular players are,” Kolodziej said. “Our studies in the fruit fly are helping us learn what some of those new players are and how they interact to make structures that are conserved in evolution.”

The adherens junction in a fruit fly isn’t exactly the same as a mammalian junction, he added, but the core components and their regulation are very similar.

In the current studies, Kolodziej and colleagues studied tracheal tube fusion during Drosophila development. The fruit fly’s network of tracheal tubes – the rough equivalent of our lungs — is critical for respiration and provides a valuable model for understanding how tubular structures like our lungs and vasculature form.

When two developing tubes meet, the cells at the tips form donut-shaped cells in the process that connects the insides of the tubes. The investigators found that a certain part of the E-cadherin protein was critical for coordinating the assembly of an internal “track” that is involved in the fusion events. This part of E-cadherin likely directs the assembly of cytoskeletal elements called microtubules through to the adherens junction, Kolodziej said.

“Cells with mutations affecting the microtubule assembly function of E-cadherin become stuck,” he said. “They can make the track, but they can’t use it to pull the surface through the cell and make the donut-shaped cell. They’re donut defective.”

The team also showed that E-cadherin recruits Short Stop, a protein that binds microtubules, to adherens junctions. Previously, the group showed that Short Stop is required for the new adherens junction to form between cells at tube tips. Together, these experiments suggest that E-cadherin and Short Stop are part of a feedback loop that leads to junction assembly.

Kolodziej and his colleagues are continuing to probe the molecular members of cell junctions and their regulation.

“You can pretty much bet that anything you find that impacts development will pop up sooner or later in human disease,” he said.

Authors of the Development paper include Mihye Lee, Seungbok Lee, and Alireza Dehghani Zadeh. The research was supported by the National Institutes of Health.