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Making One Type Of Cell By Turning Off All Other Types

The key ingredient for all multicellular life, from the simplest social ameoba to man, is the ability to create cells of different types with specialized functions.

Understanding how biology accomplishes this complex task of instructing undifferentiated cells to develop appropriately into nerve, kidney, heart muscle or any one of the thousands of different types of cells in the human body is especially important in light of the powerful new potential of stem cell technology.

If stem cells are ultimately to be used therapeutically for replacing cells that are lost through damage or disease, scientists need to know how to take a generic undifferentiated stem cell and get it to produce the required cell type, for example, motor neurons for replacement therapies for Lou Gehrig's disease.

In the current issue of Neuron, four different studies shed light on the process that the central nervous system uses to make two types of brain cells.

Two important general principles emerge. One is that, at least in the nervous system, the way you make one cell type is by turning off the ability to make all other possible cell types.

The importance of repressing other possible cell fates may be a valuable lesson in getting stem cells to do what you want.

The second important principle is that the same molecular machine can be used with one set of partners to make one cell type, in this case neurons, and then used again later with a different set of partners to make a different cell type, in this case glia.

In the first of the four papers, Ericson and colleagues demonstrate that two highly-related proteins, Nkx6.2 and Nkx6.1, are involved in making interneurons and motor neurons in the spinal cord and that both do so by turning off transcription of genes for other cell types.

In two related papers, Nakafuku and colleagues and Jessell and colleagues demonstrate that another protein, Olig 2, is required for making motor neurons and acts upstream to regulate proteins like Nkx6.2; again the main form of regulation is through repression.

In the fourth paper, elegant work by Anderson and colleagues shows that at a later stage of development, Olig 2 is also required for the generation of oligodendrocytes, a particular kind of glial cell.

How can a given region of the spinal cord sequentially produce different cell types (first motoneurons and then oligodendrocytes) using the same transcription factor? The data by Anderson and colleagues shows that this temporal switch is achieved by changes in the expression of other transcription factors with which Olig2 interacts.

Thus, when trying to make a specific kind of neuron, researchers will have to keep in mind that success depends not only on supplying the right factors, but also on excluding the right repressors.

Moreover, the work described above also indicates that a given factor may result in two different outcomes, depending on when and where it is expressed. The accompanying Minireview by William D. Richardson further describes the work and provides additional background information.

[Contact: Johan Ericson, Masato Nakafuku, Thomas M. Jessell, David J. Anderson, William D. Richardson]

13-Sep-2001

 

 

 

 

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