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The Journal of Neuroscience, April 1, 1998, 18(7):2581-2591
Sensory Cells Determine Afferent Terminal Morphology in Cross-Innervated Electroreceptor Organs: Implications for Hair Cells
Harold Zakon, Ying Lu, and Pedro Weisleder Department of Zoology and Center for Developmental Biology, Patterson Laboratory, University of Texas, Austin, Texas 78712
ABSTRACT
Top
Abstract
Introduction
Type I and type II hair cells of the vestibular system are innervated by afferents that form calyceal and bouton terminals, respectively. These cannot be experimentally cross-innervated in the inner ear to determine how they influence each other. However, analogous organs are accessible for transplantation and cross-innervation in the brown ghost electric fish. These fish possess three types of electroreceptor organs. Of these, the sensory receptors of the type I tuberous organ are S-100- and parvalbumin-positive with a calbindin-positive afferent that forms a large calyx around the organ. Neither the sensory receptors nor the afferents of the ampullary organs label with these antibodies, and the afferent branches form a single large bouton beneath each receptor cell. In controls, when cut ampullary afferents reinnervate transplanted ampullary organs, they have characteristic calbindin-negative terminals with large boutons. When type I tuberous afferents reinnervate ampullary organs, receptor cells remain S-100- and parvalbumin-negative, and the tuberous afferents still express calbindin. The nerve terminals, however, make large ampullary-like boutons on the receptor cells. These results suggest that (1) afferent terminal morphology is dictated by the receptor organ; (2) expression of calbindin by the afferent is not suppressed by innervation of the incorrect end organ; (3) ampullary organs generate ampullary receptor cells although innervated by tuberous afferents; and (4) ampullary receptor cells can be trophically supported by tuberous afferents.
Key words: tuberous organ; ampullary organ; hair cells; vestibular; cochlear; electric fish
INTRODUCTION
Vestibular organs possess two types of hair cells with different morphologies and ion conductances (Wersäll, 1956
; Correia and Lang 1990
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Figure 1. Schematic illustration of four logically possible experimental results from cross-innervation of an ampullary organ with a calyx-forming tuberous type I afferent. 1, The axon will be rejected. 2, The ampullary organ will induce the tuberous afferent to form bouton endings. 3, The tuberous afferent will induce the ampullary organ to become a tuberous organ. 4, The tuberous axon will form a large tuberous calyx on the ampullary organ.
Weakly electric fish generate electric fields to locate surrounding objects and for social communication (Bullock and Heiligenberg, 1986
Both tuberous and ampullary electroreceptor organs are found throughout the skin of the fish (Carr et al., 1982
MATERIALS AND METHODS
Surgical procedures. Brown ghosts were anesthetized with 3-aminobenzoic acid ethyl ester (Sigma, St. Louis, MO) (1:1000). The cheek and head were viewed under a dissecting microscope to locate regions of skin with the appropriate distribution of receptor organs. A small patch of ampullary organ-free skin on the cheek or the head (~0.5-2 mm2) was cut out with the tip of a scalpel blade and placed into a vial with 4% paraformaldehyde for later histological analysis. A second patch of skin containing a cluster of ampullary organs was removed from the top of the head and transplanted into the hole left by the removal of the first patch. This group is designated the cross-innervated group. A second group of fish had two ampullary organ-bearing patches removed from the head and switched into each other's place. This was to control for any nonspecific effects of the surgery on reinnervation. This group is designated the control group. The transplanted pieces of skin were held in place for a few minutes after surgery and usually remained in place. After surgery fish were revived with aquarium water and returned to their aquariums.
One week after surgery, fish were reanesthetized, and the cheek patch was viewed under the microscope to be certain that the transplant, the borders of which were demarcated by a wound margin in the epidermis, was still visible. At 2, 3, 4, or 6 weeks after the transplant, a larger piece of skin surrounding and including the transplant was removed and fixed as above.
Immunocytochemistry. Skin designated for immunocytochemical examination was fixed for 2 hr, washed in PBS, and stored in PBS at 4°C until it was examined immunohistochemically. Skin pieces were dehydrated in an alcohol series, defatted in methyl salicylate, and rehydrated. They were then brought through an acetone series to reduce nonspecific fluorescence and rehydrated. Skin patches were washed in PBS and incubated in PBS-1.0% bovine serum albumin-1.0% Triton X-100 solution and placed in primary antibody (Ab) overnight at 4°C. The next day they were washed in PBS and placed in secondary Ab for 1 hr (1:200 dilution; Cappel, Durham, NC), washed in PBS, and mounted on slides with gel mount. Pieces of skin that were double-labeled were simultaneously incubated with both primary Abs overnight and with both secondary Abs for 1 hr the next day. The sections were examined with epifluorescence optics.
The following primary antibodies and dilutions were used: 3A10 (1:1, a monoclonal antibody; Developmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA) that recognizes a neurofilament-associated protein and serves as a marker for neurites; R8701 and R302 (1:200, polyclonal antibodies; kindly donated by Dr. Kenneth Baimbridge, University of British Columbia) against the calcium-binding proteins calbindin-28 kDa and parvalbumin, respectively; and Z628, which recognizes the calcium-binding protein S-100 (Dako, Carpinteria, CA).
Organs in the skin surrounding the transplants and axons entering the transplants could be viewed clearly in whole mount. However, because of connective tissue at the base of the transplant, axons and organs within it could not be seen. The skin was trimmed down to the borders of the transplant, washed in PBS, cryoprotected in 20% sucrose in PBS overnight, frozen at
70°C in isopentane, and embedded in OCT compound (Tissue-Tek). The skin was then cryosectioned at 20 µm and mounted on microscope slides.
Electron microscopy. Skin that was to be examined with an electron microscope was placed on a Petri dish, flattened, fixed in 4% paraformaldehyde and 2.5% glutaraldehyde for 10 min, and then immersed in a small vial containing the same fixative solution. The next day, the skin was transferred to a buffer solution, post-fixed in osmium (2.0% OsO4 in NaPO4 buffer) for 1 hr, dehydrated in serial alcohols and propylene oxide, and embedded in Epon plastic (Polysciences, Warrington, PA). Ultrathin (~90 nm) tissue sections were cut with a diamond knife, stained with uranyl acetate and lead citrate, and examined and photographed with the Hitachi HU 11-E transmission electron microscope (from the Cell Research Institute, University of Texas, Austin, TX).
RESULTS
Normal anatomy of electroreceptor organs
Electroreceptor organs appear as protuberances of the epidermal layer into the dermis. The two classes of tuberous organs and the ampullary organs are distinct (Szabo, 1974
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Figure 2. Cross-sections of electrosensory organs. A, Type I tuberous receptor organ. Note the large-diameter, heavily myelinated axon at the base of the organ (arrows) and the row of free-standing sensory receptor cells with prominent nuclei (asterisk) that line the lumen of the organ. The bouton endings at the base of each receptor cell are not visible at this magnification. B, Type II tuberous receptor organs are smaller and innervated by a thinner axon. The sensory cells also have prominent nuclei. The parent axon is not in this section, but some of its branches are evident below the organ (arrows). The boutons are also not visible at this magnification. C, Ampullary organs are clustered. Their sensory receptor cells have prominent nuclei and are embedded within a support cell layer. Note their large-diameter osmophilic boutons (arrow). e, Epidermis; d, dermis. The parent axon is not in this section. Scale bar, 30 µm.
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Figure 3. Cross-sections of tuberous types I and II and ampullary organ afferents labeled with 3A10 anti-neurofilament-associated protein. Note the large calyceal terminal of the tuberous Type I afferent, the thin wispy terminals of the tuberous Type II afferent, and the large synaptic boutons of the Ampullary afferent. Scale bar, 30 µm.
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Figure 4. Whole mount of a piece of skin with a tuberous type I calyx (top) and an ampullary afferent (bottom). The fluorescently labeled axons are partially occluded by melanocytes. Tuberous type I afferents wrap around a single organ, whereas ampullary afferents innervate a number of smaller organs indicated here by a clustering of boutons. Scale bar, 60 µm.
The type II tuberous organ is smaller (60-100 µm diameter) but structurally similar to the type I organ in other regards (Fig. 2). It is innervated by a thinner axon (4-6 µm diameter), the branches of which terminate in a small bouton (2 µm) beneath each receptor cell (Fig. 3). Each tuberous organ is innervated by a single afferent, and each afferent innervates only one organ.
Ampullary organs are the smallest in diameter (30-40 µm) and are connected to the exterior environment by a canal that is devoid of cells. They possess about 8-10 sensory cells per organ that are embedded within the support cell epithelium. These sensory cells are innervated by a thin axon (2-3 µm diameter) that makes a large bouton (6-8 µm diameter) ending at the base of each receptor cell (Figs. 2-4). These organs are clustered, and an afferent innervates all the organs in a cluster (Zakon 1984
We found that the sensory cells and afferents of these organs can be further distinguished by their immunoreactivity to a panel of Abs against different calcium-binding proteins (Table 1). All tuberous sensory receptors labeled with Abs against S-100 and parvalbumin. Both classes of tuberous afferents labeled lightly with the parvalbumin Ab, but only the large calyceal afferent of the type I organ was labeled by the calbindin Ab (Figs. 5, 6). None of these Abs labeled ampullary receptors or afferents (Fig. 6).
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Table 1. Distribution of calcium-binding protein antibody labeling in electroreceptors and their afferents
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Figure 5. Whole mount of skin containing one tuberous type I and two tuberous type II afferents double-labeled with 3A10 for neurofilaments (top panel) and R8701 for calbindin (bottom panel). Only the type I afferent expresses calbindin. Scale bar, 60 µm.
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Figure 6. Cross-section of an ampullary organ labeled with 3A10 for neurofilaments (top panel) and R8701 for calbindin (bottom panel). The ampullary afferents do not express calbindin. However, calbindin is expressed by large-diameter type I afferents running in a fascicle below the ampullary organ. Scale bar, 60 µm.
Control procedures
Ampullary organ clusters were visible under a dissecting microscope, allowing us to target for removal patches of skin that appeared ampullary organ-free. Nevertheless, it was critical to verify this. All presumed ampullary-free patches were labeled with an antibody to neurofilament-associated protein to visualize axon terminals and viewed in whole mount; each patch contained tuberous organs of both types but no ampullary organs (n = 24). The patches removed from the face (2-11) contained an average of 6.8 ± 2.9 tuberous organs. The average distribution of each organ type was 3.5 ± 1.8 type I organs and 3.37 ± 1.6 type II organs per patch, which reflects their approximately equal distribution in this area of skin.
It was also critical to determine whether the surgical removal of the patch might sever ampullary axons that run through the patch but that terminate on distant ampullary organs. We tested this by removing a small patch and then immediately removing a large area of skin surrounding the hole, labeling it with the Ab to neurofilament-associated protein, and examining it in whole mount (n = 10 on the face; n = 10 on the head). In a few cases, it could be seen that removal of the skin patch severed one or two axons of passage; in all cases these were axons innervating tuberous organs adjacent to the hole. As anticipated, no ampullary organs were observed close to the hole, and the axons of distant ampullary organs were never transected when the skin patch was removed. Thus, it is unlikely that the removal of the skin patch in subsequent experiments would have resulted in transection of ampullary axons. Because each tuberous organ is innervated by a single axon, the number of organs removed (2-11) plus the few axons to neighboring tuberous organs that were severed during skin removal (2-4) is a measure of the total number of tuberous axons severed (
15).
In a previous study of electroreceptors in another species, innervation of electroreceptor organs by more than one afferent was frequently observed (25%) in large patches of regenerating skin (Fritzsch et al., 1990
Morphology of afferent terminals in control transplants on the head
As a control, we examined the morphology and immunocytochemical profile of ampullary organs in skin patches that were transplanted where an ampullary organ had been previously and where an ampullary axon was therefore without a target organ. We removed two patches of skin from the head, each containing an ampullary cluster as well as an average of 6.0 ± 3.7 tuberous organs (2-11; average type I, 2.3 ± 1.9; average type II, 4.0 ± 2.0) and switched them (n = 8). Skin patches were removed 3 or 4 weeks after transplantation, then sectioned, labeled, and examined. The receptor cells of the ampullary organs looked normal, and their afferent fibers made large bouton synapses on them. However, in none of the cases (zero of eight) were these afferents calbindin-positive, although the calyces of all the tuberous type I organs (16 of 16) in the same sections were calbindin-positive (Fig. 7).
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Figure 7. Cross-sections of two different ampullary organs from two different fish reinnervated by ampullary afferents. These organs are double-labeled for neurofilaments (NFIL) and calbindin (CALB) and are presented in pairs (A, B; C, D). Note that the afferents do not express calbindin (B, D). Scale bar, 30 µm.
Morphology of afferent terminals in cross-innervated transplants on the face
Pieces of skin surrounding an ampullary transplant were removed at 2, 3, or 4 weeks after transplantation, double-labeled with 3A10 to visualize the axons and R8701 to label calbindin, and examined in whole mount. In no cases were ampullary organs located adjacent to the transplanted patch; the closest ampullary organs were hundreds of micrometers from the transplanted skin patch, and their axons did not run through or make collateral sprouts into the patch. Thus, innervation of the ampullary organs in the transplant was not caused by collateral sprouting from afferents of organs outside the patch.
The skin was then trimmed down to the transplanted patch using the wound margins around it as a guide, and the patch was sectioned. At 2 weeks (n = 6) two ampullary organs had not yet been reinnervated; these were devoid of sensory receptors, because the receptors depend on the afferents for trophic maintenance (Szamier and Bennett, 1973
We followed afferents through serial sections to determine whether they form extensive collateral fibers en route to the organs. Afferents never showed collaterals but seemed to grow directly toward an organ. Even afferents that had not yet reached an organ appeared to be growing toward it in a directed manner, and little or no collateralization was observed along the axon, even at its leading edge.
In all cases (n = 18), at 3 and 4 weeks after transplant the ampullary organs had normal-appearing ampullary receptors and were innervated by axons with large bouton endings. Most of these afferents (17 of 18) were calbindin-positive (Fig. 8). Thus, regenerating tuberous afferents only make large bouton endings on ampullary organs.
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Figure 8. Cross-sections of three ampullary organs from three different fish reinnervated by tuberous afferents. These organs are double-labeled for neurofilaments (NFIL) and calbindin (CALB) and are presented in pairs (A, B; C, D; E, F). Note that the afferents strongly express calbindin yet show a typical ampullary large-bouton terminal morphology. Scale bar, 30 µm.
Tuberous organs in the transplanted patch were also examined to determine whether regenerating afferents made appropriate endings for each target organ (identified by the size of the organ), or whether they made large bouton ampullary-like endings indiscriminately. We found that afferents to type I organs made calyceal endings, and those to type II organs made thin bouton endings (data not shown).
In another set of cross-innervated patches examined at 3 and 4 weeks after transplantation, we labeled alternate sections with Abs against S-100 and parvalbumin to see whether the transplanted ampullary receptor cells now expressed these antigens. Although tuberous receptor cells were strongly labeled by both Abs (35 of 35 organs in eight fish) as in control fish, ampullary receptor cells were never labeled by these Abs (zero of eight) (Fig. 9).
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Figure 9. Cross-section of an ampullary organ (A, B) and a tuberous type I organ (C, D), each reinnervated by a tuberous type I afferent and labeled for neurofilaments (A, C) or S-100 (B, D). Note that the sensory receptors of the tuberous organ express S-100, whereas those of the ampullary organ do not, although reinnervated by a tuberous axon.
The boutons of transplanted ampullary organs were also examined with the electron microscope. These boutons had normal-looking synapses in which vesicles in the receptor cell are clustered around an electron-dense synaptic ribbon that makes a finger-like projection into the bouton (Fig. 10).
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Figure 10. Electron micrographs of a normal ampullary receptor cell and one reinnervated by a tuberous afferent. A, A normal ampullary receptor cell with its large terminal bouton (asterisk). B, An ampullary receptor cell in an organ that had been reinnervated by a tuberous afferent and with an ampullary-like terminal (asterisk). C, A higher-power micrograph of a typical ribbon synapse. D, A developing ribbon synapse at a regenerating tuberous afferent ampullary receptor synapse. Scale bars: A, B, 2 µm; C, D, 400 nm.
Morphology of afferents in cross-innervated transplants on the head
Because the control transplants were made on the head, and most of the cross-innervated transplants were made on the cheek, we wished to be certain that there were no location-dependent differences in reinnervation. We therefore made an additional set of cross-innervated transplants on the head. These were examined at 3 or 4 weeks after transplant and showed typical ampullary boutons, most of which (five of seven) were calbindin-positive (data not shown).
DISCUSSION
Calcium-binding proteins in tuberous receptor cells and afferents
Tuberous receptor cells labeled with Abs against S-100 and parvalbumin, whereas ampullary receptor cells did not. Vestibular and cochlear hair cells of most vertebrate groups contain various calcium-binding proteins (Rabié et al., 1983
The presence of calbindin in the type I tuberous afferent was not unexpected, because the type I tuberous receptors of Apteronotus fire phase-locked at 650-1000 Hz (Hopkins, 1976
The idea that sensory neurons that express calbindin or calretinin participate in a rapid-transmission, low-jitter pathway in electric fish is further supported by a phylogenetic analysis: neurons in the time-coding pathway of Eigenmannia that phase lock at frequencies of 250-600 Hz label with a calbindin Ab, whereas those in Sternopygus that fire at modest frequencies of 50-150 Hz do not (Losier and Matsubara, 1990
Electroreceptor sensory cells dictate afferent terminal morphology; afferents do not influence sensory cell identity
Our results suggest that when tuberous type I axons reinnervate transplanted ampullary organs, the terminal morphology of the afferent is determined by the ampullary receptor cell rather than being intrinsically determined by the afferent. This conclusion depends on proving that (1) ampullary organs were not reinnervated by ampullary axons; (2) calbindin is a selective marker for tuberous type I afferents; (3) tuberous type I axons do not form ampullary-like endings on all sensory cells whenever they regenerate; and (4) the ampullary-like terminals are not a transient step en route to the formation of a tuberous type I calyx.
First, because the patches of skin that were removed for transplant never contained ampullary organs, ampullary axons were not severed during patch removal, and ampullary axons from neighboring organs did not supply collaterals to the transplanted patch, it cannot be the case that ampullary organs were reinnervated by ampullary axons.
Second, because none (zero of eight) of the axons innervating ampullary organs in the control transplants was calbindin-positive, we can conclude that ampullary axons do not express this epitope during regeneration. This is important because some calcium-binding proteins are transiently expressed during development or regulated by activity (Braun, 1990
Third, we found that tuberous afferents that contacted tuberous organs made tuberous-type, and never ampullary-type, terminals. Thus, regenerating tuberous afferents do not by default make large bouton synapses on all cell types and do not appear to make large bouton terminals even transiently on tuberous organs.
Last, even 6 weeks after transplantation (~3 weeks after initial innervation), tuberous axon terminals still show an ampullary-like morphology, demonstrating that this is not a transient occurrence. Interestingly, the tuberous axons still express calbindin at this time. At least judging by this one marker, then, there is not a wholesale switching of phenotype, suggesting that the transformation occurs locally within the cytoskeletal matrix of the afferent terminal. We conclude that afferent terminal morphology is dictated by the sensory receptors even when the afferent previously had a different phenotype and continues to express at least one aspect of that phenotype (calbindin immunoreactivity) (Fig. 11).
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Figure 11. Summary diagram of the relationship between receptor cells, support cells, and afferent neuron. It is hypothesized that the identity of the receptor cell is determined by the support cells that give rise to it because receptor cell identity is not influenced by cross-innervation. Because sensory receptors of denervated organs die but are healthy in cross-innervated organs, a tuberous afferent can support an ampullary receptor cell. Last, it is hypothesized that the receptor cell can dictate the morphology of the afferent terminal. The fact that tuberous afferents still express calbindin suggests that the effect on the afferent is a local one at the terminal.
In addition, the fact that ampullary receptor cells cross-innervated by tuberous axons still look like ampullary receptor cells and do not express S-100 or parvalbumin suggests that the afferents do not influence the identity of the sensory receptor cells.
Tuberous axons trophically maintain ampullary receptors
Denervation of ampullary and tuberous organs results in the degeneration of the sensory receptors within either days or weeks (Roth and Szabo 1969
Comparison with hair cells and their afferents
The calyceal terminals of the tuberous afferents and large bouton endings of the ampullary afferents are most similar to the types I and II vestibular afferent terminals, respectively. The associations between types I and II vestibular hair cells and their afferent endings were originally defined by electron microscopy (Wersäll, 1956
Our other main finding, that the identity of the sensory afferent is independent of its innervation, is in agreement with results showing that types I and II vestibular or cochlear inner and outer hair cells, which are distinguishable by nerve-independent criteria such as ionic conductances and hair bundle morphology, differentiate normally in the absence of innervation (Corwin and Cotanche, 1989
Implications for central maps
Tuberous and ampullary afferents project onto different regions of the brainstem. Tuberous afferents trifurcate and innervate three separate maps, whereas the ampullary receptors innervate a distinct ampullary map (Heiligenberg and Dye, 1982
FOOTNOTES Received July 7, 1997; revised Jan. 12, 1998; accepted Jan. 19, 1998.
This work was supported by National Institutes of Health Grant DC01522. We would like to acknowledge Susan Gustavson for fish care, Gwen Gage and Kristina Schlegel for artwork, Kenneth Baimbridge and Wes Thompson for gifts of antibodies, and the Developmental Hybridoma Center for the purchase of antibodies.
Correspondence should be addressed to Harold Zakon at the above address.
Current address for Pedro Weisleder is Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013.
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