Critically Important Intercellular Communication System Discovered

 

In order to proliferate and differentiate, multicellular organisms like ourselves rely on a constant flow of information between cells. For a very long time, one of the major challenges in biology has been deciphering the language of intercellular communication. By rhythmically encoding the messages over time, researchers at Caltech have now discovered that cells have evolved a way to transmit more messages through a single pathway, or communication channel, than was previously thought. 

A paper published in the February 8 issue of Cell provides a description of the work that was carried out in the laboratory of Michael, executive officer for Biological Engineering, Howard Hughes Medical Institute Investigator, and professor of biology and bioengineering. 

The researchers focused their attention on a crucial communication system known as "Notch", which is present in nearly every animal tissue. The Notch pathway is a desirable target for drug development because it contributes to a variety of cancers and developmental disorders

Cells communicate with each other by using specialized molecules known as ligands, which interact with receptors, which are molecular antennae. Certain Notch ligands are produced on the surface of the cell that is using the Notch pathway to send instructions to its neighbors, such as instructing them to divide or differentiate into a different type of cell. 

After that, these ligands bind to Notch receptors that are embedded in the surfaces of nearby cells. This causes the Notch receptors to release transcription factors—molecules that change genes—into the cell's interior. The transcription factors activate particular genes as they travel to the cell's nucleus, where the DNA of the cell is stored. As a result, cells can alter their gene expression in response to signals from their neighbors thanks to the Notch system. 

By altering the structure of the receptors into which they dock, ligands prompt transcription factor activation. In a receiving cell, all ligands modify their receptors in the same way and activate the same transcription factors. As a result, scientists generally assumed that the receiving cell would not be able to accurately identify which ligand had activated it and, consequently, which message it had received

At first glance, the only possible explanation for how cells, if at all, differentiate between two ligands is that they must precisely detect differences in the degree to which the two ligands activate the receptor. However, according to the lead author and former graduate student in the E L O I-T Z lab, (Sandy) and (PhD '18), "cells have much more difficulty precisely analyzing incoming signals than radios or mobile phones do". 

They are usually very good at telling when a signal is present or not, but not very good at it. In this sense, texting and cellular messaging are more similar to sending warning signals. Therefore, the question is, "How can a cell distinguish between two ligands that appear to be identical puffs of smoke in the distance"?

In other words, Nandagopal and his colleagues wondered if the answer lay in the temporal pattern of Notch activation by various ligands. The team created a new video-based system that allowed them to record signalling in real time in each cell to test this. The group was able to observe how the molecules interacted while signalling was taking place by tagging the receptors and ligands with markers made of fluorescent proteins

They looked at Delta1 and Delta 4, two chemically similar N O T C H ligands, and discovered distinct patterns of receptor activation. They were able to send messages that were vastly distinct thanks to these patterns