News and Publications

Chairman's Overview

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

The major focus of the Department of Neurobiology is vertebrate development, in particular, development of the nervous system. Because the molecular processes leading to the emergence of animal form over time are just beginning to be described, no adequate theory of development exists comparable to current theories of evolution and genetics. The unfolding of modern methods of cell biology in the 1950s and 1960s and of molecular biology in the 1970s and 1980s has led to reductionist views of embryonic development that center on the cell and the gene as the functional units of development. In most inductive and morphogenetic processes in the embryo, however, the functional units are not single cells. Rather, they are collectives of interacting cells that give rise to tissues and organs. Can we reconcile a molecular analysis with the fact that form arises epigenetically from the collective interactions of an increasing number of embryonic cells during development? The key question is, How does the 1-dimensional genetic code specify a 3-dimensional animal of a given species?

Our department seeks to answer these questions at several levels by attempting to link genetic regulation to the mechanochemical processes that coordinate cell division, cell movement, and cell death. Recent studies suggest that such a link is provided by cell adhesion molecules (CAMs), which mediate cell-cell binding, and by substrate adhesion molecules (SAMs), which affect movement of cells and transformations of cell states. CAMs are involved in defining cell collectives and the borders of these groups of cells as the collectives interact during inductive events in morphogenesis. Networks of SAMs are involved in patterned cell migration. Although CAMs cannot be considered the "cause" of induction, they play major constraining roles in complex chains of inductive interactions that involve hormones and growth factors, components of the extracellular matrix, and cellular receptors.

CAMs function in neurite guidance and fasciculation, cell migration, and regeneration. Each CAM studied so far is specified by a single gene, although the genomic structures of different CAMs vary widely. The neural CAM (N-CAM), the first CAM to be characterized, is an example of a calcium-independent CAM. Detailed investigation of its structure supports the hypothesis that an N-CAM--like gene was the evolutionary precursor of a family of neurally important adhesion molecules and of the entire immunoglobulin superfamily.

Perturbation of CAM binding can lead to changes in morphology. Moreover, these changes (e.g., in nerve-muscle regeneration) lead to alterations in the expression of CAMs, suggesting that a series of readjustments in signaling events controls the expression of CAMs. During morphogenesis and regeneration, CAMs are coregulated with SAMs to affect cell migration and positioning. An example is tenascin, an extracellular matrix protein that supports counteradhesive events. This molecule may be one of a series of molecules controlled by neural signals that affect migration of cells and neurites into particular sites.

Expression of CAMs and SAMs is regulated by place-dependent dynamic signaling that is essential to normal neural morphogenesis. Understanding how such morphoregulatory molecules are regulated at the level of the gene is essential. Our studies indicate that transcription factors critical in development (Hox and Pax proteins, in particular) are involved in regulating the expression of CAMs. We have also obtained direct evidence that CAM-mediated adhesion itself can influence gene expression.

The key accomplishments of the past year are summarized in the reports that follow. Highlights include production and use of N-CAM knockout mice to show that the N-CAM promoter is regulated by neural activity, demonstration that the neural restrictive silencer DNA element is critical for neural specific expression of the CAM L1, detection of kinase signaling pathways and N-CAM domains involved in astrocyte proliferation and gene expression, and determination of domains of tenascin and their receptors involved in the migration of glioma cells.

All these findings raise a number of questions that continue to be addressed by members of the department. What gene products or combinations of gene products control the expression of CAMs and SAMs in embryogenesis and differentiation? When cells adhere through particular adhesion molecules, what signals are sent back to the genome to change the pattern of differentiation? Which domains of adhesion molecules carry out the various biological functions of the molecules? Attempts to answer these questions are at the center of the research currently being done by the members of our department.