Neurobiology

Chairman's Overview

Gerald M. Edelman, M.D., Ph.D.

For the past decade, the Department of Neurobiology has focused its efforts on primary cellular processes of development, with emphasis on the development of the vertebrate nervous system. This work began with our research leading to the identification and characterization of cell adhesion molecules and studies on factors that regulate cell division. The results of these efforts and the development of new technologies prompted us to examine the control of fundamental processes of gene expression in eukaryotic cells. These processes involve factors that regulate gene transcription as well as those that regulate the translation of messenger RNA into protein. Analysis of these processes has enabled us to examine the development of the nervous system at more fundamental levels. We have, for example, been studying the nature and differentiation of neural stem cells and the molecular mechanisms that underlie long-term potentiation, a key process in memory and learning. Understanding such multilevel integration in complex systems is becoming a crucial challenge in modern biology. Clearly, molecular events are so interconnected that a reductionist approach alone, while valuable, is insufficient for understanding biological systems.

Development and morphogenesis require repeated rounds of differential gene expression. A variety of factors regulate this expression, including elements within the genes themselves and protein factors that bind to the elements. In examining such elements in genes for cell adhesion molecules, Fred Jones and his colleagues discovered a homeobox protein, Barx2, that affects a wide variety of differentiation processes. Exploration of the activity of Barx2 and its targets by Robyn Meech has opened new front lines related to breast cancer, muscle development, and chondrogenesis.

In examining the messenger RNAs expressed in response to neural cell adhesion, Vince Mauro noted that many mRNAs had sequences that matched or were complementary to ribosomal RNA. By analyzing a subset of these sequences, he and his colleagues defined the characteristics of novel sequences within mRNAs that can connect the translation machinery to the message in the absence of the traditional cap sequence. These internal ribosome entry sites (IRESs) were known for viral RNAs but had not been extensively defined in cellular mRNAs. Dr. Mauro and his colleagues went on to show that cellular and viral IRESs differ; the cellular sites are made up of small modules, and the action of cellular IRESs does not necessarily depend on specific secondary structures in the mRNA.

Regulation of translation appears to play an important role in the nervous system, and IRESs may play a special role in the functioning of the synapse. Peter Vanderklish and his colleagues have been studying the factors involved in synaptic events thought to provide the basis of memory and learning in the area of the brain called the hippocampus. Translation of mRNA in dendrites plays a special role in this process. Dr. Vanderklish and his colleagues found that specific messages at the synapse are differentially translated depending on whether the messages are regulated by cap- or IRES-dependent processes. In addition, these researchers are working with Bruce Cunningham and his colleagues to define and characterize granules containing ribosomes, proteins, and mRNAs that are transported from the cell body to the synaptic area in order to allow translation to occur in response to synaptic activity.

The development of the nervous system begins with the differentiation of stem cells to neural progenitors, which in turn develop at the proper time and place into neurons and supporting glia.

Moreover, neural progenitor cells remain in the brain in adults, where they presumably repopulate specific brain regions. Kathryn Crossin and her colleagues found that the neural cell adhesion molecule N-CAM can act as a neurotrophin to differentiate the neural stem cells preferentially into neurons. Moreover, using special multielectrode plates, they defined conditions under which a stem cell population in culture can be converted into neurons capable of exchanging action potentials in a functioning neural network.

All of these activities are aimed at the study of the molecular and cellular events that define and regulate the development of the nervous system. Our efforts have remained focused on fundamental processes rather than on specific diseases. This strategy is based on the belief that understanding even a single primary process can provide the necessary framework for defining the mechanisms underlying not just one but a variety of diseases.