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Journal of Neuroscience, Vol 15, 6767-6778, Copyright © 1995 by Society for Neuroscience
Tissue- and age-specific expression patterns of alternatively spliced agrin mRNA transcripts in embryonic rat suggest novel developmental roles
DM Stone and K Nikolics
Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
Agrin is an extracellular matrix protein that mediates the nerve- induced
clustering of nicotinic acetylcholine receptors on target muscle cells, and
thus plays a key role in development of the neuromuscular synapse.
Alternative exon usage within the rat agrin gene predicts numerous protein
isoforms, which differ by the inclusion or exclusion of small inserts at
three sites in the C-terminal half of the molecule; the insert status at
two of these sites, termed Y and Z, profoundly influences the acetylcholine
receptor clustering activity. We have examined the cellular expression
patterns of agrin messenger RNA transcripts during rat embryogenesis by in
situ hybridization with isoform-specific probes. Six 36-mer oligonucleotide
probes were designed to distinguish between mRNA isoforms at either the Y
site: the encoded protein contains either no insert (Y0) or a 4-amino acid
insert (Y4), or the Z site: the encoded protein contains either no insert
or one of 8 (Z8), 11 (Z11), or 19 (Z19) amino acids. Strikingly different
expression patterns were observed for the individual Y- and Z-site encoding
messages. While optional exon usage predicts the possibility of eight
different agrin isoforms at the two splice sites, we detected only four
isoforms in vivo: Y4Z0, Y0Z0, Y4Z8, and Y4Z19. The Y4Z0 transcript, which
comprised the majority of the agrin expressed, was localized exclusively to
nervous tissue and exhibited a distribution profile suggestive of a
potential role in neurogenesis and/or neural differentiation. From
embryonic day 13 to birth, Y4Z0 was found in mitotic ventricular zones,
spinal, cranial, and sympathetic ganglia, and diffusely throughout the
brain. In contrast, Y0Z0 was not expressed in neurons, but specifically
labeled capillary endothelial cells within the developing nervous system.
Y4Z8 and Y4Z19, the forms most active in acetylcholine receptor
aggregation, were expressed at low levels only in spinal and brainstem
motor neurons; Z19 expression declined from embryonic day 15 to adulthood,
whereas Z8 expression increased slightly during this period. Transcripts
encoding the Z11 insert could not be detected. These data suggest potential
novel biological roles for agrin beyond that originally proposed in synapse
formation.
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