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Christopher A. Walsh Laboratory 

Focus - January 23rd, 1992

Cell Milieu Directs Cortex Development
Drs. Cepko and Walsh Trace Progeny of Developing Brain Neurons

By Kenneth B. Chiacchia

The development of growing cells in the cortex of the brain is influenced more by interaction with the cells' environment than by intrinsic genetic cues, conclude Harvard Medical School researchers. The scientists, Drs. Constance Cepko and Christopher Walsh, have been studying for several years how cells learn what to become during development. They have shown that the descendants of single progenitor cells in the developing brain can end up in distant structures of the cerebral cortex, performing widely different functions*. In deciding where to migrate and how to differentiate, the developing cortical nerve cells must be responding to external signals, they suggest.

"One thing is certain," notes Dr. Cepko, HMS associate professor genetics, "a mother cell does not tell all of its daughters to go to a particular functional domain. Presumably, while newly generated cells are migrating, or after they arrive at their destination, they are getting information about how to differentiate by interacting with neighboring cells, or other environmental signals."

A central question in developmental biology, says Dr. Cepko, has been whether neighboring cells in the brain's structures are descended from a common progenitor, or "mother" cell, or whether they migrate and develop in response to interactions with their neighbors. "It is a question of environment versus lineage," she says. Adds Dr. Walsh, HMS research fellow in genetics, "It is a general problem in developmental biology but also might have eventual relevance to such disorders as brain malformations and epilepsy." Dr. Walsh is also a neurologist at Mass. General Hospital.

Nature vs. Nurture

The question of "nature versus nurture" - whether the mind's psychological structure is more a product of inborn qualities or of life experiences - has fascinated thinkers since ancient times. But as scientists have begun to uncover how the single cell of a zygote leads to the many complex structures in an organism, a similar controversy has arisen over how the physical structure of the brain is determined. Do the neurons of the developing brain have inborn genetic instructions that dictate where they will go and what functions they will carry out? Or do signals from other cells orient them, causing them to grow in a way that gives rise to the intricate networks of connections that comprise the brain?

Previous studies using more primitive parts of the brain indicated that descendants of neurons remained clustered together to form brain structures, suggesting that internal genetic cues are more important for the development of those parts of the brain. Work with lower organisms, such as the fruitfly Drosophila melanogaster, had indicated that relatively tight genetic control restricted developing neurons. "Segments of the Drosophila embryo, including the compartments of the brain, correspond to cell lineage," says Dr. Walsh, with single progenitor cells giving rise to clusters of nerve cells in the same location and with the same structure and function. The hindbrain of vertebrates - the most primitive structure of the brain and the part responsible for basic functions like eating, breathing, and sleeping - "shows a similar compartmentalization, with lineage compartments corresponding to the structural segments" that give rise to such structures as the cerebellum and the medulla oblongata.

Uniqueness of Cortex

The situation has not been as clear in the cerebral cortex, where different experiments yielded contradictory results. The largest part of the human brain, the cortex is the location of higher brain activity, the residence of intelligence and memory, among other functions. "It is what we think of as the most uniquely human part of the brain," states Dr. Cepko. For this reason, and because fetal development of body structures often gives scientists clues as to how they developed evolutionarily, developmental biologists have been keenly interested in how the cells of the cortex know how and where to specialize into their final functional forms.

New Technique

The only way to address this question - whether descendants of progenitor cells give rise to discrete functional units or whether they intermingle more widely across the cortex - was to develop a new technology, says Dr. Walsh. By infecting progenitor cells in the developing rat brain with a number of slightly varied retroviruses, he explains, the scientists could label them. Descendants of the labeled cells could be identified by the differences in the viral DNA they had inherited from their ancestors.

The gene they engineered into the retroviruses was that for beta-galactosidase, an enzyme which turns the labeled cells blue. By using a mixture of 100 retroviruses containing different DNA "markers" near the galactosidase gene, the researchers were able to introduce a molecular fingerprint that could be identified later on. "We could just cut out a chunk of tissue and amplify DNA from a single labeled cell using PCR (the polymerase chain reaction process by which trace amounts of DNA are multiplied and analyzed)," states Dr. Walsh.

Surprising Result

The researchers were surprised to observe where the descendants of the labeled neurons wound up in the developing cortex: while offspring of a single cell were often clustered together, a large proportion could be found dispersed from one end of the cortex to the other, according to Dr. Walsh. While clusters of cells descended from a single progenitor were all found to reside in a single functional compartment in the hindbrain, such descendants in the cerebral cortex usually end up in different functional domains. "These descendants have a lot of different functions," he says.

With the apparent lack of internal instructions for how the neurons will develop, developmental direction "has to arise from intracellular interactions," states Dr. Walsh. "A piece of the cortex doesn't know whether to be part of the auditory or visual structure unless it is told what to do." Dr. Cepko expands, "This means that the instructions they are receiving are coming from other cells. The cells that give the signals probably arose much earlier in the evolution of the brain and most likely some are non-cortical cells. The progenitors that make up the cortex are a population of cells responsive to such signals." The next step, says Dr. Walsh, will be to identify the cells that send out these signals, and how their message is carried to the developing cortical neurons.

Evolutionary Lessons

Developmental and evolutionary biologists have derived many important lessons from each others' disciplines. The finding of the relative importance of environmental signals in the development of cortical neurons provides tantalizing hints as to how the cortex evolved, says Dr. Cepko. Both the shape and size of the cortex evolved very recently, she adds, and the question of how the cortex - both that of the rats examined in these studies and that of humans - arose and from whence came higher brain function may be one and the same. These results, she believes, "could imply something about its evolution. We found that the progenitor cells are not programmed to provide a certain number of cells to go to a certain place. The plan is not hard-wired into the genome.

The absence of a genetically-determined plan "may have provided flexibility in terms of development," adds Dr. Walsh. The cortex, he says, may have constituted a neurological structure that could be "adapted to the particular needs of the organism. " The researchers postulate that the plasticity of the cortex may have aided evolution somehow, allowing relatively fast physical development to meet the challenges faced by mammals as they evolved. This, in turn, may prove an important piece of the evolutionary puzzle of how and why human intelligence developed.

*"Widespread Dispersion of Neuronal Clones Across Functional Regions in the Cerebral Cortex." Christopher Walsh and Constance L. Cepko. Science, January 24, 1992


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