Notch effect ‘converts’ stem cells into cells of the nervous system

Discovered in 1919, Notch is a protein that can pass a signal from a neighbouring cell and change activity of genes. It causes a mutation in fruit flies that gives them notches on their wings. Such mutants also have many more neural cells than normal flies.

Now stem cell scientists at the University of Edinburgh in Scotland have discovered that Notch directs unspecialised embryonic stem cells to become cells of the nervous system. A stem cell is an unspecialised cell that has the ability to multiply without limit, and can also give rise to specialised cell types in the body. An embryonic stem cell originates from the early embryo and has the potential to make most cell types both in the body and in the laboratory.

These unexpected findings from Edinburgh pave the way for using lab-grown cells to model disease and test the effects of new drugs, and are published online in the

open-access journal Public Library of

Science (PloS) Biology.

While embryonic stem cells have the potential to make all 200 cell types in the body, the challenge is to restrain this diversity and uncover the signals that commit stem cells to a single specialised function. Sally Lowell and her colleagues have now established that Notch gives embryonic stem cells the critical push towards becoming cells of the nervous system.

The researchers show that when Notch is activated in embryonic stem cells, up to 90percent of the cells in the dish become nerve cells. In any colony of embryonic stem cells, under normal conditions, many never become cells of the nervous system: they spontaneously change into other cell types or remain as embryonic stem cells.

The Notch effect can be observed in both mouse and human embryonic stem cells, and can be created without any recourse to genetic engineering – all it takes is the presence of Notch activating signals in the cells that stem cells grow on.

As individual embryonic stem cells become specialised, they communicate with those around them. Notch is a major means of communication, and has, according to Lowell: “A domino effect: once it is switched on in a small group of cells, it sets off a wave of Notch activation in neighbouring cells, directing them all to become cells of the nervous system.”

This research has far-reaching implications for other aspects of stem cell research. “We expect our findings to shed light on how to make other types of cell, such as muscle or pancreatic cells. If we can identify the processes that Notch blocks in embryonic stem cells we will have a handle on how to get them started, and so drive embryonic stem cells to become other types of cell that are more difficult to grow in the lab,” adds Lowell.

Says professor Austin Smith, leading the Edinburgh team and coordinating the EuroStemCell consortium: “This discovery gives us another method to generate pure populations of nerve cells – so important for drug screening, disease modelling and potential cell therapies. As in stem cell colonies, communication between EuroStemCell researchers has been crucial to this discovery. Our work would not have been possible without information and materials from colleagues in Cambridge, Paris and Stockholm.”

EuroStemCell is a four-year integrated project of the European Union’s Sixth Framework Programme, and will receive up to E11.9million in funding from the EU. The 27 participating laboratories are from Scotland, England, Sweden, France, Denmark, Italy, Germany, and Switzerland. They comprise universities, research institutes and three biotechnology companies. EuroStemCell’s mission is to build the scientific foundations required to take stem cell technology to the clinic.

Crucial to the success of this project is work carried out at the Wellcome Trust Sanger Institute which developed antibodies that allowed researchers to detect Jagged, a binding partner – ligand – for Notch in cell-to-cell communication.

Within its ‘atlas of protein expression’ group, the Institute’s researchers can generate stem cell identification reagents by creating recombinant antibodies using phage display.

One approach involves the isolation and characterisation of antibodies by cell surface selection.

A second strategy uses recombinant proteins as a source of developmentally important antigens for the generation of antibodies.

By applying this dual approach, the group aims to generate combinations of antibodies that will be useful in the teasing apart of stem cell differentiation and proliferation pathways, and in the further molecular characterisation of stem and differentiating progenitor cells arising from them.

The Notch family and its associated ligands Delta and Jagged are an example of this. The pathway is evolutionarily conserved and, in mammals, is central to a wide array of developmental processes including hematopoiesis, somitogenesis, vasculogenesis, and neurogenesis. These processes involve maintenance of stem cell self-renewal, proliferation and specification of cell fate.

By generating panels of antibodies against Notch family member proteins, the expression of these antigens in stem cells and their differentiating progeny may be more closely studied.

Moreover, patterns of particular protein expressions during emryogenesis can be established. For example, anti-Notch antibodies have been selected on recombinant protein, sub-cloned into optimised expression vectors, and a panel of unique antibodies have been used to stain murine embryos at 14.5 days of development.

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