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Thanks, Phil Tompkins, for the news that "Gerald Fischbach, chairman of Harvard Medical School's neurobiology department, has been appointed the new director of the National Institute of Neurological Diseases and Stroke effective July 30." Will he decide which PD grants will be funded? or can the grant review committees override him? A new director usually means a fresh start, which may mean renewed hope for us. Below is Prof. Fischbach's Harvard website describing the research that he himself has been doing with his own group. Would those Listmembers who are scientifically literate take a look at it, and give us plain folk some feedback? His work may not be directly related to PD. But one of his recent papers concerned "Neurotrophic factors". And in his research summary, he says, "Our principal goal, at the present time, is to characterize the role of trophic factors that promote the differentiation and survival of nerve cells and the targets they innervate." Does that mean what I hope it might mean -- that we may have a new supportive champion at NIH? someone whose own professional interests might include a push for the cure? Should we do something to welcome him? Mary Yost, 50/diag.1990 [log in to unmask] **************************************************************** http://neuro.med.harvard.edu/http/fischbach/fisch.html Gerald D. Fischbach, M.D. Chairman & Professor Dept. of Neurobiology 220 Longwood Ave. Boston, MA 02115 Tel: 617-432-2510 Fax: 617-432-3223 [log in to unmask] This laboratory studies the function and the formation of chemical synapses. Our principal goal, at the present time, is to characterize the role of trophic factors that promote the differentiation and survival of nerve cells and the targets they innervate. Acetylcholine receptors (AChRs) are concentrated in the postsynaptic membrane at the neuromuscular junction and at interneuronal synapses. At the developing junction, this remarkable specialization is due to a local increase in AChR synthesis and also to the aggregation of AChRs already present on the cell surface. AChR synthesis and aggregation are induced by factors that are probably released from the motor nerve terminal. We have purified a protein from the brain that induces the synthesis of AChRs in embryonic myotubes, and we have found that this Acetylcholine Receptor Inducing Activity (ARIA) does, in fact, accumulate at developing synapses. In addition to its effect on AChRs, recombinant ARIA also increases the synthesis of voltage-gated sodium channels, another protein that is concentrated in the postsynaptic membrane at nerve-muscle synapses. Thus, ARIA may regulate the expression of several synapse-specific genes in a coordinate manner. Molecular cloning experiments showed that ARIA is a member of a family of proteins that are ligands for transmembrane receptor tyrosine kinases. The kinases are related to the EGF receptor. Other members of the ligand family have been cloned. All of the iso-forms are the products of a single gene, with differences between them accounted for by alternative mRNA splicing. One isoform that is relevant to our work is called Glial Growth Factor (GGF) because it was purified (by others) based on its ability to stimulate the proliferation of Schwann cells. Metabolic labeling studies have shown that ARIA is synthesized as a transmembrane pre-cursor. All biological functions of the ligand family appear to depend on an EGF-like domain that is located in the extracellular part of the molecule adjacent to the transmembrane segment. Other domains may modulate this active region. We suggest that ARIA is transported rapidly from the cell body to the nerve terminal and exposed on the cell surface; then the EGF-like peptide is cleaved from the precursor by one or more proteases. ARIA was purified from the brain. We have found that the gene is expressed in all cholinergic neurons and that certain isoforms activate tyrosine kinase receptors in target neurons that bear AChRs. Studies of nicotinic and muscarinic ACh receptor regulation in the brain are under way, as are studies of long-term changes in synaptic efficacy. ARIA is also expressed as some non-cholinergic neurons and in germinal zones that contain proliferating precursor cells. This pleotrophic factor may, therefore, influence the determination of cell fate and the early stages of histological differentiation. Neuregulin gene is expressed in spinal cord motor neurons. Both panels show a cross-section through half of a chick spinal cord. The section was prepared from an 11-day embryo in situ hybridization with an antisense ribo-probe against the entire extracellular domain of neuregulin is shown on the right. The fluorescence micrograph on the left shows that neuregulin protein is abundant at this stage of development. Midal and lateral motor pools are labeled. Selected publications: Falls DL, Rosen KM, Corfas G, Lane WS and Fischbach GD (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu-ligand family. Cell 72:801-815. Corfas G, Rosen KM, Aratake H, Krauss R and Fischbach GD (1995) Differential expression of ARIA isoforms in the rat brain. Neuron 14:103-115. Goodearl ADJ and Fischbach GD (1995) ARIA is concentrated in the synaptic basal lamina of the developing chick neuromuscular junction. J. Cell Biol. 130(6):1423-1434. Loeb JA and Fischbach GD (1997) Neurotrophic factors increase neuregulin expression in embry-onic ventral spinal cord neurons. J. Neurosci. 17(4):1416-1424. Fischbach GD and Rosen KM (1997) ARIA: Neuromuscular junction neuregulin. Ann. Rev. Neurosci. 20:429-458. Sandrock AW, Dryer SE, Rosen KM, Gozani SN, Kramer R, Theill LE and Fischbach GD (1997) Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276:599-603.