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Journal of Neuroscience, Vol 7, 3489-3504, Copyright © 1987 by Society for Neuroscience
Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns
MJ Carden, JQ Trojanowski, WW Schlaepfer and VM Lee
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Monoclonal antibodies (mAbs) to rat neurofilament (NF) proteins NF-L, NF-M,
and NF-H were used to examine the developmental programs of NF expression
in rat embryos. The ability of these mAbs to recognize differentially
phosphorylated states of NF-M and NF-H (Lee et al., 1987, the preceding
paper) was exploited in order to examine the temporal and spatial patterns
of NF phosphorylation during early neuronal development in vivo. NF
proteins were first detected on the twelfth day postfertilization (E12)
using NF-L- or NF-M-specific mAbs. By E13, the coexpression of NF-L and
NF-M was widespread, reflecting dramatic increases of immunoreactivity to
both subunits. Partial phosphorylation, denoted P[+], of NF-M was already
present in perikarya and neurites of E12 neurons. Extensively
phosphorylated, or P[+++], isoforms of NF-M appeared in E13 axons, thereby
establishing a proximodistal gradient of NF phosphorylation during the
earliest phase of NF expression. Immunoblots of tissue homogenates revealed
that most NF-M of E13 embryos exists in a partially phosphorylated, or
P[+], isoform. Unequivocal staining for NF-H first appeared at E15, a time
at which NF-L and NF-M had already attained their adult patterns of
immunocytochemical staining. Levels of NF-H were extremely low at E15 but
could be detected in all of its differentially phosphorylated states, i.e.,
nonphosphorylated P[-], partly P[+], and highly P[+++] phosphorylated
isoforms. P[+++] isoforms of NF-H were restricted to the distal portions of
E15 axons, although staining of more proximal axons, like those in adult,
was noted by E17. Immunoblots of E17 embryos revealed most NF-H as P[-] and
P[+] isoforms. Quantities of immunoreactive NF-H increased very slowly and
remained well below those of NF-M and NF-L for several weeks beyond birth.
These results show that sequential forms of NFs are expressed by developing
and maturing neurons throughout the nervous system. An "immature" form of
NFs, composed of NF-M and NF-L, appears to function in establishing the
neuronal phenotype and in initiating and maintaining neurite outgrowth.
Addition of NF-H confers a "mature" state to the NF. This delayed
expression of NF-H is a slow and graduated process that coincides in time
with the stabilization of neuronal circuitries and may be important in
modulating axonal events, such as the slowing of cytoskeletal transport and
the growth of axonal caliber.
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