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The Giovanni Armenise-Harvard Foundation Session 4: Development Overview As the presentations in this session suggest, scientists often rely on animal models to shed light on the complexities of human development. The topics covered here include genetic determination of cell fate and morphogenesis, formation of neural maps in the embryonic brain, gene dosage and myelination in the peripheral nervous system, and diversification of fiber types during the development of skeletal and cardiac muscle.
The Xenopus frog is one of the classic models for studying how the three germ layers of the early embryo give rise to the organs and systems of the adult. Dr. Kirschner discussed the identification of signals that regulate cell fate and how these signals promote morphogenesis. This study focused on regulatory factors that arise in the mesoderm, but then act on adjacent ectoderm to encourage the formation of the neural tube-the precursor of the nervous system. So far, the researchers have cloned numerous genes in their studies of the structure and function of regulatory components. In this presentation, Dr. Kirschner concentrated on two: XOMBI is a gene that is involved in morphogenesis, and CYRANO determines the competence of embryonic ectoderm to form the neural plate.
The connections between the eye and brain are so specific that if they are experimentally rearranged in an animal, the creature will no longer be able to make sense of what it sees. These tight connections between retinal axons and the optic tectum (the part of the brain that interprets visual signals) are thought to be governed by neural maps established early in development. Over the years there have been various hypotheses about how these maps are made. In this presentation, Dr. Flanagan described a new family of receptors and ligands that appear capable of guiding the proper wiring of neuronal connections. In the 1960s, the leading theory was that each axonal neuron carried a specific molecular address on its surface, that these were readable by corresponding molecules on individual brain cells, and that this led each cell to make the right connection. Unfortunately, the number of unique addresses needed for this system far exceeds the number of genes available to code for them. This realization gave rise to the idea that instead of having unique molecular tags, incoming optic neurons had varying quantities of the same tag. The idea was that address information was probably spread across the incoming fibers in a concentration gradient, which was mirrored by a reverse gradient of identifying information spread across cells of the optic tectum. This would provide spatial coordinates that would enable each incoming neuron to find its place in the brain. It is this hypothesis that Dr. Flanaganâs work supports. In the optic tectum, his group found a molecule that they call ELF-1. They subsequently discovered that ELF-1 binds to a receptor, now called Mek 4, found on retinal neurons that map to the tectum. Even more importantly, ELF-1 is distributed over the tectum in a gradient as is Mek 4 in the retina. These gradients are complementary, and are present during the phase of embryonic development when the eye and brain make their connections.
Myelin is the essential insulator that enables an action potential to travel swiftly and efficiently from a nerve cell to a muscle. Without myelin, this electrical message would slow down or be lost as it traveled the length of the axon. In the peripheral nervous system myelin is formed by Schwann cells; in the central nervous system it is the work of oligodendrocytes. The expression of myelin-specific genes is carefully regulated since too much or too little of this essential substance leads to neurologic disorders such as multiple sclerosis or, less frequently, to rare herditary conditions such as Charcot-Marie-Tooth disease. Close control of these genes is also important because if Schwann cells detect an excess of one gene product, they appear to turn off other myelin-producing genes.
These researchers used transgenic mice to study dose response to the gene for P0 glycoprotein, a cell adhesion molecule, which accounts for at least 50% of the protein in myelin-forming Schwann cells in peripheral nerve. When extra copies of the P0 glycoprotein gene resulted in a 30% increase in P0 expression, peripheral nerve myelination became noticeably less efficient. Thus it appears that normal myelination depends on precise dosage, even of a protein as abundant as this one. Dr. Wrabetz and his colleagues have since engineered a new transgene, mP0TOTA, which they plan to use to create mouse models of Charcot-Marie-Tooth 1B, a neuropathy that results from mutations of the human P0 gene.
In the earliest stages of embryonic development, both skeletal and cardiac muscle start out as mesoderm. And although they remain similar in certain ways, such as being striated instead of smooth, they become progressively more different as development progresses. Dr. Schiaffinoâs interest is in identifying factors responsible for the diversification of fiber types during skeletal muscle development, and in determining how muscle genes are regulated by nerves and by activity. The researchers are also studying how genetic factors shape the development of the chambers of the heart. Using transgenic mice in which the gene for troponin I can be manipulated, they are studying transcriptional regulation of genes involved in cardiac embryogenesis.
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Identification of new regulatory components in mesoderm and
neuronal patterning
