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The Journal of Neuroscience, November 1, 1998, 18(21):8912-8918
Expression of Ciliary Tektins in Brain and Sensory
Development
Jan
Norrander1,
Magnus
Larsson2,
Stefan
Ståhl2,
Christer
Höög3, and
Richard
Linck1
1 Department of Cell Biology and Neuroanatomy,
University of Minnesota, Minneapolis, Minnesota 55455, 2 Department of Biochemistry and Biotechnology, Kungliga
Tekniska Högskolan, S-100 44, Stockholm, Sweden, and
3 Department of Cell and Molecular Biology, Center for
Genomics Research, Karolinska Institutet, S-171 77, Stockholm, Sweden
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ABSTRACT |
Many types of neural tissues and sensory cells possess either
motile or primary cilia. We report the first mammalian (murine testis)
cDNA for tektin, a protein unique to cilia, flagella, and centrioles,
which we have used to identify related proteins and genes in sensory
tissues. Comparison with the sequence database reveals that tektins are
a gene family, spanning evolution from Caenorhabditis
elegans (in which they correlate with touch receptor cilia) and
Drosophila melanogaster, to Mus musculus
and Homo sapiens (in which they are found in brain,
retina, melanocytes, and at least 13 other tissues). The peptide
sequence RPNVELCRD, or a variant of it, is a prominent feature of
tektins and is likely to form a functionally important protein domain.
Using the cDNA as a probe, we determined the onset, relative levels,
and locations of tektin expression in mouse for several adult tissues
and embryonic stages by Northern blot analysis and in
situ hybridization. Tektin expression is significant in adult
brain and in the choroid plexus, the forming retina (primitive
ependymal zone corresponding to early differentiating photoreceptor
cells), and olfactory receptor neurons of stage embryonic day 14 embryos. There is a striking correlation of tektin expression with the
known presence of either motile or primary cilia. The evolutionary
conservation of tektins and their association with tubulin in cilia and
centriole formation make them important and useful molecular targets
for the study of neural development.
Key words:
brain; C. elegans; centriole; chemo-/mechano-/olfactory-/touch-/photo-receptor cells; choroid plexus; cilia; cytoskeleton; Drosophila; microtubule; olfactory
epithelia; retina; RPNVELCRD-peptide; tekin; testis
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INTRODUCTION |
Many types of neural tissues
and sensory cells are highly ciliated (Peters et al., 1976 ; Stommel et
al., 1980; Wheatley, 1982; Alberts et al., 1994). Motile cilia of
ependymal cells generate the movement of CSF in the CNS
of vertebrates, and motile cilia of statocyst hair cells form the basis
for the detection of gravitational balance in invertebrates. Moreover,
primary cilia (generally considered nonmotile) are widespread among
neurons, sensory cells, and supporting cells in many animal phyla,
providing structural support and possibly other functions. Thus, the
functions of cilia in neural tissues and sensory cells deserve study
yet only a few of their protein components have been characterized. The
main structural component of cilia is the microtubule protein tubulin.
The tubulin family includes at least 12 isoforms in vertebrates (cf.
Joshi and Cleveland, 1990; Wilson and Borisy, 1997). In addition,
tubulin may be posttranslationally modified by (de)acetylation,
(de)tyrosination, glutamylation, glycylation, and phosphorylation
(MacRae, 1997). The in vivo functions of these diverse
tubulin isoforms and modifications are not well understood, and to
underscore this puzzle, simple organisms can assemble the complex
microtubule arrays of cilia from a single   -tubulin dimer isoform
(James et al., 1993). Ciliary movements are driven by the microtubule
motor proteins dynein and kinesin (Gibbons, 1995; Beech et al., 1996;
Porter, 1996; Bost-Usinger et al., 1997; Cole et al., 1998; Kreis and
Vale, 1998; Pazour et al., 1998), which exist as multiple isoforms
within a given cell and which are responsible for retrograde and
anterograde axonal transport, respectively (Brady and Sperry, 1995;
Kreis and Vale, 1998). Last are the tektin proteins (Linck, 1990),
which are relatively specific to cilia (and related organelles).
Tektins were originally characterized from sea urchins in which three tektins (A, ~53 kDa; B, ~51 kDa; C, ~47 kDa) form specialized filaments of the axonemal microtubules of cilia, flagella, and centrioles (Linck et al., 1985; Linck and Stephens, 1987; Steffen and
Linck, 1988; Pirner and Linck, 1994; Nojima et al., 1995; Norrander
et al., 1996). Tektins are thought to function in providing for the
stability and structural complexity of axonemal microtubules.
We noted previously the similarity of sea urchin tektins to an
expressed sequence tag (EST) clone from human brain tissue (Norrander
et al., 1996). This observation prompted our interest in developing
suitable probes that could be used to better investigate cilia in
complex neural tissues. We report here the cloning of the first
mammalian (murine) tektin cDNA. This sequence, together with recent
data from GenBank, allows us to construct an evolutionary scheme for
tektins and to correlate their presence with sensory cells. Then,
experimentally, we used Northern blot analysis and in situ
hybridization to identify and localize tektin expression in several
adult and embryonic brain and sensory tissues of the mouse.
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MATERIALS AND METHODS |
Cloning procedures. In a previous study of messenger
RNAs expressed by mouse testis meiotic germ cells, a 294 nucleotide EST (MTEST638) was found to have significant sequence similarity to tektins
from sea urchin embryonic cilia (Yuan et al., 1995). In this report, we
used a partial cDNA clone (yran4) and standard procedures (Sambrook et
al., 1989) to screen an adult mouse testis  ZapII library, from which
we obtained a full-length cDNA, MT14. The DNA Sequencing and Synthesis
Facility at Iowa State University (Ames, IA) performed automated
sequencing.
Northern blot analysis. Multiple tissue Northern blots were
obtained from Clontech (Palo Alto, CA). Inserts from the clones MT14
and yran4 were isolated on low-melt agarose gels and radiolabeled using
Rediprime DNA Labeling System (Amersham, Arlington Heights, IL). Blots
were prehybridized in 50% deionized formamide, 5× SSPE (see Sambrook
et al., 1989), 10× Denhardt's solution, 100 µg/ml sheared
salmon sperm DNA, and 2% SDS at 42°C for 3 hr. Hybridizations were
performed in prehybridization solution plus 1 × 106 cpm/ml of probe at 42°C for 16 hr. Blots were
washed as follows: 2× SSC (see Sambrook et al. 1989) and 0.05% SDS at
room temperature for 40 min with several changes of solution; and then
0.1× SSC and 0.1% SDS at 50°C for 40 min with one change of
solution. Results were analyzed by autoradiography.
Preparation of probes for in situ hybridization.
In situ probes were transcribed from linearized DNA
using either the T7 promoter-T7 RNA polymerase (antisense RNA)
or T3 promoter-T3 RNA polymerase (sense RNA). The transcription
reaction contained 1 µg of linearized template DNA, 80 mM
HEPES, pH 7.5, 12 mM MgCl2, 10 mM NaCl, 10 mM DTT, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM GTP, 0.184 mM UTP,
100 µCi [-35S]UTP, and 20 U of enzyme. Reactions
were performed at 37°C for 1 hr. DNA was removed from the reaction
using RNase-free DNaseI, and the probe was reduced to an average size
of 100 nucleotides by controlled alkaline hydrolysis.
In situ hybridizations. Mouse embryo and adult testis
sections, fixed in buffered paraformaldehyde and embedded in paraffin, were obtained from Novagen (Madison, WI). Slides were dewaxed with
xylene and then rehydrated via a series of 5 min washes in 100, 95, 70, 50, and 30% ethanol. Slides were immersed in 0.2N HCl (to disrupt
ribosomes and to make the mRNA more accessible for hybridization),
deproteinated using Proteinase K, and acetylated (to block free amino
groups that can bind probe nonspecifically) by immersion in 0.1 M triethanolamine-HCl, pH 8, followed by the addition of
0.25% acetic anhydride. Slides were equilibrated in 50% formamide,
0.6 M NaCl, 10 mM Tris-HCl, pH 7.5, 1 mM EDTA, 50 µg/ml heparin, and 10 mM DTT.
Prehybridization was performed in equilibration solution with the
addition of 10% polyethylene glycol 8000 and 1× Denhardt's solution
at 50°C for 1 hr. Hybridizations were performed in prehybridization
solution with the addition of 0.5 mg/ml carrier DNA, 0.5 mg/ml tRNA,
and 107 cpm/slide of RNA probe. Twenty-five to 50 µl of hybridization solution was placed on each slide, and a
siliconized coverslip was glued on top to prevent evaporation.
Hybridization was performed at 50°C for at least 18 hr. Coverslips
were removed by immersion in 2× SSC at 50°C. Slides were washed as
follows: 2× SSC and 10 mM -mercaptoethanol
(ME) at 50°C for 30 min; 2× SSC, 10 mM ME, and 20 µg/ml RNase A at 37°C for 30 min; 2× SSC, 50% formamide, and 10 mM ME at 50°C for 30 min; 0.2× SSC, 14 mM ME, and 0.07% sodium pyrophosphate at 50°C for 60 min with one change of wash solution.
Autoradiography. Air-dried slides were initially used to
expose Hyperfilm-Max (Amersham) to obtain low-resolution
autoradiographs and to estimate the length of exposure time. Slides
were dipped in Kodak NTB-2 Nuclear Tracking Emulsion (Eastman Kodak,
Rochester, NY) and exposed at 4°C for 10-14 d (5 times longer
than the film exposure time). Slides were developed in Kodak
Dektol developer diluted 1:1 with water, rinsed, and fixed in Kodak
Fixer.
Counterstaining and mounting. Fluorescent counterstaining
was performed by incubation for 5 min in 0.001% Hoechst
solution, followed by two 5 min washes with water. Slides were
mounted with DPX (Fluka BioChemika, Ronkonkoma, NY).
Microscopy and image processing. Microscopy was performed
using an Olympus BX-60 microscope (Olympus Optical, Tokyo, Japan). Images were taken with an Optronics CCD camera (Optronics Engineering, Goleta, CA) and captured using MetaMorph software (Universal Imaging Corporation, West Chester, PA). Fluorescent images were captured in
gray scale for optimal resolution and colored to match the wavelength
of Hoechst using Photoshop software (Adobe Systems, San Jose, CA).
Stage-specific embryonic tissues were identified by reference to
Kaufman (1992).
Sequence analysis. Sequence analysis was performed
using the Wisconsin Sequence Analysis Package (Genetic Computer Group, Madison, WI) .
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RESULTS |
The murine testis cDNA MT14 contains 1408 nucleotides, encodes a
full-length protein with a mass of 49,567 Da, and has a high degree of
homology with tektins (Fig. 1). We first
present the analysis of the sequence and then use MT14 as a probe for
Northern blot and in situ hybridization studies.
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Figure 1.
Comparison of tektin protein sequences from
C. elegans, Drosophila, sea urchin, mouse
and human. Black and gray blocks indicate
residues that occur in one or more sea urchin tektins (A1, B1, or C1)
and at least one mammalian sequence. Red blocks indicate
regions of greatest homology (i.e., identities) among the tektins
listed, including the peptide sequence RPNVELCRD, which is identically
conserved in all sea urchin tektins, mouse MT14, and human infant
brain; red regions are underestimates of complete
identity, because differences in ESTs may represent sequencing errors.
The peptide sequence RPNVELCRD shows some divergence in C.
elegans (RPGIELCND) and Drosophila
(RPNVENCRD). Also note the four highly conserved cysteines at
positions 330, 404, 553, and 614, referenced to C.
elegans. Sequence data were obtained as follows: C.
elegans, from C. elegans Genome Sequencing
Project, GenBank accession number U53337 (locus CELR02E12);
Drosophila, GenBank accession number AC002021; sea
urchin tektin A1, GenBank accession number M97188 (Norrander et al.,
1992); sea urchin tektin B1, GenBank accession number L21838 (Chen et
al., 1993); sea urchin tektin C1, GenBank accession number U38523
(Norrander et al., 1996); mouse MT14, this report and GenBank accession
number AF081947; human fetal retina, GenBank accession number AA487397;
human adult retina, GenBank accession number H86604; and human infant
brain, GenBank accession numbers T78294 and T10082.
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The first comparison of tektin A, B, and C sequences revealed that,
within sea urchins, tektins are a related set of proteins with a common
predicted fibrous structure (Norrander et al., 1996). Our present study
is the first to report a full-length mammalian cDNA, showing that
tektins represent an extended family of proteins and genes with
characteristic features. The predicted polypeptide sequence and
structure of MT14 (Fig. 1) matches most closely with sea urchin tektin
C in terms of identical (48%) and conservatively substituted (60%)
residues; the homology between MT14 (mouse tektin C) and sea urchin
tektin C is greater than the similarity between any pair of sea urchin
tektins (A, B, or C). Like tektin C, the MT14 polypeptide chain is
predicted to form extended rod homodimers with five major coiled-coil
segments interrupted by short nonhelical linkers. Among the potentially
important residues conserved between sea urchin and mouse (and human,
see below) is the peptide RPNVELCRD, which is present in the last
nonhelical linker of the polypeptide chain. In addition, there are four
conserved cysteines, each occurring in nonhelical linkers and C
terminus; the positions of the cysteines (in sea urchins) suggested
that they function to stabilize (via disulfide bonds) interactions
between tektins and/or between tektins and tubulin (Norrander et al.,
1996)
A search of the GenBank data base revealed additional sequences that
have a high degree of similarity and identity to tektins (Fig. 1),
including genomic clones from Caenorhabditis elegans and
Drosophila and numerous human ESTs from 15 different fetal, infant, and adult tissues, including brain, retina, melanocytes, testis, kidney, liver-spleen, B-lymphocytes, lung, pregnant uterus, multiple sclerosis lesions, and various tumors. Many of the clones shown contain cysteines in the conserved positions. One of the human
ESTs from infant brain spans the region containing the exact RPNVELCRD
peptide. From database searches, this peptide sequence appears only to
be present in tektin-related proteins; it is therefore a signature
sequence for tektins and is likely to form a functionally important
domain. Nearly identical peptide signatures are found in
Drosophila and C. elegans genomic clones, where
instead they are RPNVENCRD and RPGIELCND,
respectively. Besides this consensus domain, 17 other individual
residues are invariantly conserved throughout the polypeptide chains of
tektins selected from C. elegans, Drosophila, sea
urchin, mouse, and human (Fig. 1).
The sequences of the human ESTs isolated from different tissues differ
somewhat from MT14. Some of these differences could result from a more
error-prone sequence within the ESTs. Alternatively, the divergent
tektin-related ESTs could correspond to new tektins or to other members
of the tektin gene family identified in sea urchins (e.g., to tektins A
and B). ESTs with divergent but tektin-related sequences have been
mapped to three different chromosome locations in the human genome. A
retinal tektin EST (GenBank accession number G27368) maps to human
chromosome 15, and two other tektin-related ESTs are located on
chromosomes 11 (GenBank accession number AC000382) and 21 (GenBank
accession number HSJ003295). These data support the notion that
multiple tektin-related genes are also present in mammals.
Given the emerging sequences of tektins, and particularly those from
human brain, retina and melanocytes, we were interested in examining
the potentially wider presence and developmental importance of tektins
in adult and embryonic vertebrate neural tissues by analyzing the
expression of tektin transcripts in mouse. Blots of
poly(A+) RNA isolated from eight different adult
tissues (testis, lung, brain, heart, kidney, liver, skeletal muscle,
and spleen) were probed with testis tektin cDNA MT14 (Fig.
2a). Transcripts hybridizing with MT14 were clearly detected in testis, lung, and brain. A band of
~1550 nucleotides was detected in lung and brain, and bands of
~1550 and ~4000 nucleotides were visible in testis; the relative
abundance of transcripts in these tissues is evident (Fig.
2a). To examine the possible expression of tektins during embryonic development, blots containing poly(A+) RNA
isolated from embryonic day 7 (E7), E11, E15, and E17 embryos were probed with mouse testis tektin cDNA clone yran4 (Fig.
2b). A band of ~1550 nucleotides is first detected in E11
embryos, and its level increases in E15 and E17 embryos.
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Figure 2.
Northern blot analysis of mouse adult and
embryonic tissues. a, Poly(A+) RNA
from eight different adult tissues were probed with MT14. Bands of
~1.5 kb are visible in testis, lung, and brain. In addition, a 4.0 kb
band is present in testis. b,
Poly(A+) RNA from four stages of mouse embryonic
development were probed with yran4. A band of ~1.5 kb is visible in
increasing amounts starting at 11 d. Lanes
contained equal amounts of poly(A+) RNA (2 µg) and
relatively constant levels of the control -actin transcript (data
not shown).
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To determine the location of tektin expression in mouse embryos,
in situ hybridization experiments were performed using
35S-labeled MT14 antisense RNA, and as controls, labeled
sense strand RNA for MT14 and antisense RNA for protamine were
used (a protein only expressed in testis during spermatogenesis)
(Zambrowicz et al., 1993; Wykes et al., 1995). We first examined
embryonic stages at E8, E10, E12, E14, and E16, which revealed specific
areas of labeling beginning at E12. To analyze more carefully the
location(s) of tektin expression in the embryonic brain, we focussed on
serial sagittal sections of E14 embryos. Specific labeling with
antisense MT14 was localized to several neural tissues: (1) the choroid plexus of the lateral and fourth ventricles of the brain, (2) the
developing retina, and (3) the olfactory epithelia (Fig.
3). No labeling was seen in embryos with
negative controls, i.e., the sense strand RNA for MT14 or the antisense
strand RNA for protamine (Fig. 3). In the retina, most of the labeling
occurred in the primitive ependymal zone (cf. Sidman, 1961). In this
region of the mouse retina at stage E14, cells committed to becoming photoreceptors are just beginning to proliferate (Turner et al., 1990;
Altshuler et al., 1991). Although we cannot positively identify the
labeled cells as early photoreceptors, we tentatively identify them as
such, because photoreceptor cells will develop primary cilia (see
below). Similarly, labeled cells of the olfactory epithelia are most
likely developing olfactory receptor neurons, which will also elaborate
long primary cilia.
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Figure 3.
In situ hybridizations of E14 mouse
embryos (sagittal sections, paraformaldehyde-fixed).
a-c represent serial sections of the lateral brain
ventricle showing a Hoechst-stained fluorescence image
(a) and specific hybridization in the developing
choroid plexus (b, c,
arrows) with MT14 antisense RNA. c, No
labeling is seen in tissues of an adjacent section probed with
protamine antisense RNA. Scale bar (in a), 250 µm. d-f represent serial sections of the eye showing
a Hoechst-stained fluorescence image (d),
hybridization of MT14 antisense RNA in the developing retina
(e, f, arrows), and
absence of hybridization using MT14 sense RNA
(f). Scale bar (in d),
250 µm. g (Hoechst-stained) and h
(hybridization with MT14 antisense RNA) show enlarged views of the
retina. Scale bar (in g), 50 µm. i and
j represent a section of olfactory epithelium
(arrows) showing Hoechst-stained fluorescence image
(i) and specific hybridization with MT14
antisense RNA (j). Protamine antisense RNA failed
to label olfactory epithelium (data not shown). Scale bar (in
i), 250 µm.
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DISCUSSION |
The above results from the Northern blot and in situ
hybridization analyses demonstrate that tektin C-related transcripts are differentially expressed in specific neural tissues during mouse
development. We can best explain the tissue-specific expression of
tektins by their association with ciliary microtubules.
Tektins form specialized filaments associated with the nine outer
doublet microtubules of cilia and flagella; more specifically, tektin
filaments are associated with a set of three chemically stable
protofilaments of the A-microtubule wall, located near the inner
junction with the B-tubule (Linck et al., 1985; Stephens et al., 1989;
Linck, 1990; Nojima et al., 1995). Tektin filaments are composed of
core protofilaments assembled from tektin A and B heterodimers; tektin
C is thought to form homodimers assembled onto the periphery of these
core protofilaments or to form a second separate tektin filament
(Pirner and Linck, 1994). The association of tektins and tubulin may
form the basis of the high degree of stability of doublet microtubules,
and in addition, the location of tektin filaments in A-tubules and
their periodic longitudinal spacings suggest that they may provide
positional information for the attachment of inner dynein arms, radial
spokes, nexin links, and/or the inner connection with the B-tubule
(Stephens et al., 1989; Linck, 1990; Pirner and Linck, 1994; Nojima et
al., 1995; Norrander et al., 1996); however, these postulated functions have yet to be demonstrated directly. As predicted from their structural roles, all three tektins, A, B, and C, are coordinately expressed during ciliogenesis (Norrander et al., 1995). In addition to
the role of tektins in ciliary structure, immunoblot and
immunofluorescence studies with species ranging from sea urchins and
mollusks to humans strongly imply that tektin filaments extend from
similar or identical filaments in basal bodies and centrioles (Steffen and Linck, 1988; Hinchcliffe and Linck, 1998; Stephens and Lemieux, 1998).
Based on the structural role of tektins, their expression in the organs
and tissues observed here (Fig. 3) correlates with the presence of
motile cilia and/or primary nonmotile cilia. The choroid plexus of the
ventricles of the brain is lined with ciliated ependymal cells (Peters
et al., 1976), which function in the surface transport of CSF to and
through the central canal (also ciliated) of the spinal cord.
Vertebrate retinal photoreceptors and olfactory receptor cells possess
nonmotile primary cilia (Alberts et al., 1994). In invertebrates, e.g.,
C. elegans (Perkins et al., 1986) and Drosophila
(Keil, 1997), primary cilia are associated with mechano-receptors
(touch-receptors). Whereas the Drosophila clone shown
in Figure 1 could represent a tektin gene for either mechanoreceptor cilia, sperm flagella, or centrioles, the C. elegans clone
probably represents a tektin for touch receptors or centrioles, because C. elegans sperm do not contain microtubule-based flagella
(Ward et al., 1986). Ciliary axonemes certainly act as rigid structural supports for photoreceptors (i.e., the connecting cilium between inner
and outer rod segments) and for the cellular extensions of chemo-,
osmo- and mechano-receptor membrane processes, and axonemes appear to
provide the motile machinery for transport of molecular components to
and from the receptor terminus (Beech et al., 1996; Cole et al., 1998).
In addition, electrophysiological evidence from statocyst cilia
suggests that ciliary axonemes play an active role in transmitting
mechanical stimuli (Stommel et al., 1980; Stommel and Stephens,
1988), with dynein-mediated tension (but not motility per se) being
required for membrane depolarization. The possible roles of tektins, as
mentioned earlier, may be to form and stabilize the ninefold array of
doublet and triplet microtubules. The potential role of tektins in
generating the attachment sites for dynein arms and spokes may not be
used in primary sensory cilia, which appear to lack these components;
however, the frequency of occupancy of these sites is not known, and
the presence of a small number of dynein arms might be required for
sensory function.
A number of questions and experimental possibilities emerge from this
work. First, it is important to determine the extent of the tektin gene
family (e.g., in Mus musculus), to determine whether they
are differentially expressed during development, and to determine the
functions of the conserved sequence elements. In retina, expression of
cilia-related genes might provide an earlier means of detecting the
onset of photoreceptor development compared with opsin expression
(Knight and Raymond, 1990; Watanabe and Raff, 1990; Altshuler et al.,
1993; Neophytou et al., 1997). Ciliogenesis may also provide cues in
the development and regeneration of olfactory receptor neurons from
basal cells (Graziadei and Graziadei, 1993; Whitesides et al.,
1998). Finally, tektins may be useful targets for analyzing the role of
ciliary microtubules in signal transduction and diseases of sensory
cells, as well as how primary cilia function in developing neurons in
which the occurrence of primary cilia is widespread (Dahl, 1963;
Wheatley, 1982, 1995).
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FOOTNOTES |
Received June 29, 1998; revised Aug. 6, 1998; accepted Aug. 17, 1998.
This work was supported by USPHS Grant GM35648, National Science
Foundation Grant DBI-9602237, March of Dimes Birth Defects Foundation
Grant FY96-0741, Minnesota Medical Foundation Grant SMF-155-95, and
University of Minnesota Graduate School Grant 17212 (to R.L.); the
Swedish Natural Sciences Council and the Karolinska Institutet
(to C.H.); and the Swedish Research Council for Engineering Sciences
(to S.S.). We thank Eva Brundell, Aimee deCathelineau, Dr. Maureen
Riedl, Li Yuan, and the lab of Dr. Martin Wessendorf for expert
technical assistance, and Drs. Robert Elde, Paul Letourneau, and Steven
McLoon for valuable discussions and critical readings of this
manuscript.
General correspondence should be addressed to Dr. Richard Linck,
Department of Cell Biology and Neuroanatomy, 4-144 Jackson Hall,
University of Minnesota, 321 Church Street, Minneapolis, MN 55455.
E-mail addresses: norra001{at}maroon.tc.umn.edu (J.N.),
magnus{at}biochem.kth.se (M.L.), stefans{at}biochem.kth.se (S.S.),
christer.hoog{at}cmb.ki.se (C.H.), linck{at}lenti.med.umn.edu (R.L.)
Dr. Norrander and Dr. Larsson contributed equally as first authors.
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Top
Abstract
Introduction
