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]

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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.