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Stem Cells and Neural Development

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admin 发表于 2002-12-22 22:39:00 | 显示全部楼层 |阅读模式




Stem Cells and Neural Development




 

David J. Anderson, Ph.D.

Investigator,

California Institute of Technology



Biography...


 
 
 

Arteries aligned with peripheral sensory nerves...




 
 
 

Cross section of a mouse spinal cord...




 
 
 

Isolation of a neural stem cell...




 
 
 

Embryonic blood vessel network...




 
 
 
 

Summary: David Anderson is studying the development of neural stem cells, the genetic control of neural cell fate, and the embryonic development of arteries and veins.



Stem cells are primitive, undifferentiated cells that have the capacity both to reproduce themselves (self-renew) and to differentiate into specialized cell types, such as neurons or muscle cells. A fundamental problem in neural development is to understand how the stem cells of the nervous system produce all the different types of cells composing the adult brain. These include different subtypes of neurons and of nonneuronal cells called glia. Our approach is to isolate neural stem and progenitor cells, characterize their developmental capacities, and identify some of the molecules and genes that control their differentiation from outside and inside the cell. Our principal accomplishments in recent years have been (1) the direct isolation of neural stem cells from uncultured tissue and the development of an in vivo transplantation assay for these cells, (2) the identification and functional analysis of "master genes" that control neuronal differentiation, and (3) the identification and functional analysis of a new family of related master genes that sequentially control neurogenesis and gliogenesis. We have also pursued studies in the field of angiogenesis, stemming from our discovery that arteries and veins are molecularly distinct from the earliest stages of blood vessel formation.



Isolation and Characterization of Neural Stem Cells

A fundamental issue in neural stem cell biology is to understand how many different kinds of neurons and glia a single stem cell can produce. We have developed procedures to identify and isolate neural crest stem cells directly from uncultured tissue, based on their selective labeling by antibodies that bind specific proteins on the cell’s surface. Using these markers, we can use fluorescence-activated cell sorting to purify the stem cells away from the other, unwanted cell types. We can then examine the differentiation capacities of these stem cells by challenging them with various differentiation signals in petri dishes or in host embryos.



How many and what types of specialized cells can neural stem cells isolated in this manner generate? Transplantation of the cells into host embryos provides a powerful complement to in vitro studies in petri dishes. We have developed a method to test the capacities of isolated rat neural crest stem cells by transplanting them directly back into host chick embryos, which are more accessible than mammalian embryos. Remarkably, the transplanted rat stem cells intermingle with their chick counterparts and migrate to appropriate locations after they are injected. The freshly isolated cells can make both neurons and glia, just as they can in vitro, but they can make only certain types of neurons and not others. This indicates that some neural stem cells may become restricted in the subtype of neuron they can generate before they have decided whether to differentiate to neurons or to glia.



Knowing that the isolated stem cells can make at least certain kinds of neurons and glia (as well as smooth muscle), we returned to our petri dishes to ask how the stem cells choose among these different fates. Are these decisions made on "autopilot," according to some internal genetic program, or do they depend on the cell’s local external environment? We found that the cells choose their fate according to their environment, and we identified several specific proteins, or growth factors, that, when added to the culture medium, push the stem cells to select a given differentiated fate from their menu of options. Some factors promote neuronal differentiation, others promote glial differentiation, and still others promote smooth muscle differentiation.



The fact that neural stem cell fate can be predictably manipulated by such environmental signals does not mean that these cells are simply blank slates, however. We found that the cells are inherently predisposed to respond to certain environmental instructions and that these intrinsic biases change with time. Early in the process, for example, stem cells are more sensitive to neuron-inducing signals than to glial-inducing signals, while later they are more sensitive to the glial-inducing signals. This makes biological sense, since neurons usually differentiate before glia during neural development. Recent studies suggest that some of these changes in sensitivity can be explained by changes in the relative levels of expression of the receptors that bind and interpret neuron- and glial-inducing signals.



Master Genes for Neuronal and Glial Differentiation

We have identified several master switch genes for the neuronal fate. Expression of these genes in stem cells is sufficient to drive their differentiation to neurons. Are there similar master switch genes for the glial fate? Recently, we identified the Olig genes, a new family of genes that, in combination with a partner gene, Nkx2.2, are sufficient to drive the differentiation of stem cells to oligodendrocytes, the myelin-forming glia of the central nervous system. Independent work from the laboratory of Thomas Jessell (HHMI, Columbia University College of Physicians and Surgeons) has shown that Olig genes can promote differentiation of motor neurons at earlier stages of development. Thus, Olig genes sequentially promote the differentiation of motor neurons, and then oligodendrocytes, from a common pool of progenitor cells, by changing partners at different stages. More recently, we have shown that deletion of the Olig genes in mice prevents differentiation of both motor neurons and oligodendrocytes. This loss reflects a fate-conversion event, rather than simply a failure of differentiation. Spinal cord precursors lacking Olig genes generate certain kinds of interneurons and astrocytes (another type of glial cell), rather than motor neurons and oligodendrocytes. Thus, Olig genes seem to link the choice between two alternative subtypes of neuron to the choice between two alternative subtypes of glia.



Novel Receptors for Pain-Sensing Neurons

Sensory neurons, which derive from the neural crest, innervate the skin and mediate responses to touch, pressure, heat, cold, and painful stimuli. In the course of identifying new marker genes for these neurons, we discovered a large family of novel genes, called Mrgs, that encode receptors expressed on the cell surface. The Mrgs appear to be expressed by sensory neurons and no other cell type in the body. Although the exact molecules recognized by these "orphan" receptors is not yet known, they appear to be able to bind neuropeptides, short proteins that can modulate neuronal function. An exciting possibility is that the MRGS modulate pain sensitivity, in which case they could prove useful as targets for new analgesic drugs.



Identity Specification and Patterning of Developing Arteries and Veins

Several years ago, we discovered serendipitously that arteries and veins are molecularly distinct, and that bidirectional interactions between these two types of blood vessels are essential for proper circulatory system development. We have now exploited our ability to distinguish arteries and veins molecularly to investigate when and how these differences arise during development. Using these tools, we have recently discovered that in developing skin, the branching pattern of arteries, but not veins, is aligned with that of peripheral nerves. In the absence of nerve fibers, arteries fail to differentiate properly. Moreover, mutations that change the branching pattern of the nerves change that of arteries as well. These data suggest that signals from the nerve are required for proper arterial differentiation in the skin, and that the branching pattern of peripheral nerves provides a "template" to pattern the branching of arterial blood vessels.



Grants from the American Heart Association, the National Institutes of Health, and the March of Dimes supported portions of this work.





Last updated: November 25, 2002



 楼主| admin 发表于 2002-12-22 22:40:00 | 显示全部楼层
http://www.hhmi.org/research/investigators/anderson.html
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