Department of Neurobiology

The major focus of the Department of Neurobiology is vertebrate development, in particular development of the nervous system in relation to neural function. Because the molecular processes leading to an adult animal 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 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.

Members of the department are seeking to understand molecular, cellular, and chemical aspects of the development and function of the nervous system. It brings to bear all the modern techniques of biology and chemistry to a key question: How does the one-dimensional genetic code specify a three-dimensional animal?

One important question in the development and morphology of the nervous system is how collectives of interacting cells and cell products give rise to the complex connectivity of the brain. The department has long had a program studying the effect of cell adhesion molecules (CAMs) on cells in the central nervous system. The neural cell adhesion molecule (N-CAM), discovered in 1978, was the first CAM to be characterized. N-CAM mediates cell-cell interactions in development and in adult tissues, and its binding induces a variety of intracellular signals, including those leading to changes in gene expression.

A number of the department's faculty study the effect of CAMs on morphogenesis. One investigator looks at the structure and function of CAMs by using biochemical and molecular biological techniques to examine the interactions of the domains or parts of N-CAM. In collaborative studies, the three-dimensional structures of the domains using nuclear magnetic resonance are also studied.

Other investigators examine the regulation of CAM genes, and the effect of this regulation on neural morphogenesis. They study the regulatory regions of the CAM genes and transcription factor families like the Hox and Pax proteins, which regulate CAM expression. In recent years, they have designed and used a new method for constructing synthetic promoters to study transcription in different cell types and states. They have also obtained direct evidence that CAM-mediated adhesion itself can influence gene expression.

An important discovery was made recently when one research group found that by adding N-CAM to neural stem cells, the stem cells can be transformed into neurons. When they put the stem cells together with N-CAM, the stem cells developed into neurons in the normal several week span that development takes in a test tube, and at the end of this period the neurons began to fire.

This result may one day point the way to novel treatments for a number of neurodegenerative diseases by suggesting a method to regenerate neurons. Cellular therapy, in which neural stem cells are implanted to treat conditions like Parkinson's disease, has shown only limited success because most of the implanted cells don't become neurons. But investigators in the department were able to bias these stem cells to become neurons—in vitro—as high as 90 percent of the time. Therapy aside, this work has also provided a wealth of follow-up topics, such as determining the mechanisms that influence the emergence of firing activity.

Another important area of research has been the control of protein synthesis by ribosomes—the molecular machines that synthesize proteins from messenger RNA (mRNA). When genes are expressed, they are first transcribed into an mRNA, which then is transported to another part of the cell where it is translated into protein. Protein synthesis occurs when a ribosome "reads" an mRNA and uses it as a template to synthesize a protein chain. But nothing in life is ever that simple.

Ribosomes must interact with mRNAs to function, and these interactions are controlled by initiation factors. The initiation factors, conglomerating around a "cap" consisting of a methylated guanosine-nucleotide on the end of the mRNA strand, attract all but the larger subunit of the ribosome to the mRNA, and move to the first three-letter codon, which says "put amino acid X here." Once there, the larger ribosomal subunit is recruited and begins to make proteins.

One group in the department highlighted a further level of control of this highly regulated molecular factory—internal sequences in the untranslated or non-protein coding regions of mRNA that can recruit the ribosome.

These so-called internal ribosomal entry sites (IRESes) are small stretches of nucleotides contained within the mRNA molecules that can help attract ribosomes. They appear to do this because the nucleotides in the IRESes are complementary to corresponding nucleotides in the ribosome, much of which is also RNA. The IRES RNA binds to the ribosomal RNA through base pairing, similar to the way that two strands of DNA bind to each other.

The investigators found that multiplying the number of small IRES-modules in an mRNA resulted in a large increase in protein translation and a dramatic increase in the amount of protein generated. This tremendous amplification of output may have potential applications in gene therapy and in biotechnology.

This work also suggests a more sophisticated way of understanding the translation of genetic messages. In this model, there are enhancers and inhibitors within the mRNA that influence protein synthesis. Different mRNA molecules with different IRES combinations may form a competing population for translation, allowing the cell to preferentially translate one message over another.

The overall goal of the department is to understand the fundamental molecular and cellular mechanisms that regulate neural development, which have significant implications for the diagnosis and treatment of a wide range of diseases.

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