Life Sciences, Vol. 54, No. 18, pp.

1291-1297, 1994
Pergamon Copyright © 1994 Elsevier Science Ltd
Printed in the USA. All rights reserved
0024-3205/94 $6.00 + .00

MINIREVIEW

N E U R O T R O P H I N S AND T H E D E V E L O P M E N T OF C O C H L E A R
INNERVATION

G6rard Despr6s and Raymond Romand

Laboratoire de Neurobiologie et Physioiogie du D6veloppement,

Universit6 Blaise Pascal, 63177 Aubi&e Cedex, France.
(Received in final form February 10, 1994)

Summary
The rapid progress in the past few years concerning neurotrophic factor research, has
greatly stimulated advances in developmental neurobiology of hearing. We have
summarized evidence that neurotrophins are expressed by auditory sensory epithelia during
the time at which ganglion cells with neurotrophin receptors send their processes to these
epithelia. Recent findings have led to the identification of BDNF and NT3 as responsible
substances. Since no NGF mRNA nor the NGF high affinity receptor component trkA
mRNA were detectable during the development of cochlear structures, this factor is not
likely to be an important neurotrophin at this level. By their biological activity,
neurotrophins could be responsible for chemotrophic, differentiation, survival, and
maintenance functions at the afferent as well as at the efferent level of the inner ear
development.

Key Words: neurotrophins, cochlea, auditory function

The onset of auditory function depends predominantly on the establishment of precise connections
between the cochlear hair cell receptors and neurons of the statoacoustic ganglion. Several molecules
may be involved in the establishment of these connections. Some of them may correspond to tropic
and/or trophic factors. The history of neurolropic and trophic factors in the inner ear began 85 years ago
with Ramon y Cajal (1) when he studied the peripheral development of auditory nerve fibers. He
described wandering bundles of fibers that grew incessantly turning in obtuse or right angles before
perforating a specific zone of the otocyst. Because he did not find any pathway in the environment
along which the axons moved, he proposed that the orienting factor was a diffusible neurotropic
substance that emanated from a discrete region of the otic epithelium. Since these pioneering
descriptions, the reality of such a form of chemotaxis was confirmed in the recent years by the
identification of several molecules including the neurotrophin family. The mere presence of these
molecules is not sufficient, however, for understanding of the complex mechanisms underlying growth
of auditory nerve fibers. Numerous arguments suggest that the guidance of nerve fibers and nerve target
interactions could happen via a preformed adhesive pathway (2). Adhesive molecules such as NCAM
(neural cell adhesion molecule), fibronectin or laminin could be implicated in such interactions (3-5).

Although both aspects of pathfinding are probably closely related, we will focus here on the
intervention of neurotrophins in the inner ear development, since they probably play a role not only in
chemotrophic interactions but also in the maintenance and survival of peripheral as well as central
neurons. In most mammals the mature sensory and neural complement of the inner ear consists of two
types of auditory receptors, the inner and outer hair cells innervated by two afferent and at least two
efferent fiber systems (see ref. 6):
-the afferent innervation is composed of peripheral processes from the local spiral ganglion cells
which are of two types. The large type I spiral ganglion ceils (about 95% of the total) make connections
with inner hair cells; the smaller type II ganglion cells (about 5% of the total) make connections with
outer hair cells.
1292 Neurotrophins and Cochlea Vol. 54, No. 18, 1994

-the efferent innervation originates from two locations. First, neurons of the lateral superior
olivary complex project mainly to the ipsilateral cochlea and terminate beneath inner hair cells. Second,
neurons located near the medial superior olivary complex project principally to the contralateral cochlea
and terminate on outer hair cells. In the cochlea, efferent fibers are regrouped in the intraganglionic
spiral bundle, which passes along the spiral ganglion.

Thus developmental events have to proceed in complex interactions which have to guide, select
and maintain at least four different innervation systems (Fig. 1).

OHCs IHC

IIJ ll~ III Ih

ii. i ...
Superior
olivary
complex

Cochlear
Nucleus
BRAINSTEM

Spiral Ganglion

Fig. 1

In the cochlea, developmental events have to proceed in complex interactions

which have to guide, select and maintain specifically at least four different
innervation systems. The two types of auditory receptors, inner hair cells (IHC)
and outer hair cells (OHCs), are innervated respectively by one afferent and at
least one efferent fiber system (see Ref. 6). The afferent innervation is composed
of peripheral processes from the local spiral ganglion cells which are of two
types. Type I (TI) spiral ganglion cells are connected with IHC, type II (TII)
ganglion ceils with OHCs. The efferent innervation comes from two locations.
Neurons of the lateral superior olivary complex (LSO) proiect mainly to the
ipsilateral cochlea and terminate beneath IHC. Neurons located near the medial
superior olivary complex (MSO) project principally to the contralateral cochlea
and terminate on OHCs.

Interactions between the sensory epithelium and the afferent innervation system
Briefly, in the early mouse embryo (see ref. 6-8), the inner ear develops at the lateral
rhombencephalic level from a placode which, at embryonic day (E) 8-E9, invaginates and separates
from the ectoderm to finally give rise to the otocyst around El0. The otocyst differentiates into sensory
and non-sensory otic epithelium as well as into the statoacoustic ganglion (SAG) which migrates from
the otic epithelium. SAG cells then divide and differentiate into discrete cochlear (spiral) and vestibular
(Scarpa's) ganglia. Peripheral processes of these neurons enter their respective sensory epithelia around
E l 2 and make synapses with hair cells during the neonatal period. Their central processes connect to
the brainstem at the cochlear nucleus level for auditory nerve fibers or vestibular nuclei for vestibular
fibers. The precise period of synaptogenesis at this level is still unknown.

Most of the information about the mechanism of formation of afferent innervation comes from in
vitro observations on cultured embryonic inner ears. Although some abnormalities during organotypic
development are noted, ultrastructural and biochemical observations on the maturation of sensory hair
Vol. 54, No. 18, 1994 Neurotrophins and Cochlea 1293

cells and ganglion cells have suggested that these structures are able to form functional links and to
replicate in vitro their in vivo ontogenic maturation (7-8). However, we must be aware that under in
vitro conditions, even in optimum settings, embryonic neurons develop without the infuences of the
central target fields. This situation may induce these cells to express or repress certain metabolic
pathways which can disrupt the natural way of development.

Studies of organotypic cultures of mouse-embryo inner ears have suggested, in agreement with
Cajal's hypothesis, that otocysts provide a chemotropic signal to attract SAG fibers (9). In coculture
conditions, SAG peripheral processes can grow to the sensory epithelium of an intact otocyst as well as
to an isolated sensory (otic) epithelium (10). Moreover, when trigeminal ganglia where cocultured with
otic epithelia, trigeminal fibers were attracted by the sensory epithelia suggesting that a pluripotent
substance was produced by the target tissue. The tropic interaction disappeared after the neurites had
penetrated the wall of the otic sensory epithelium (10). In the chick embryo, organ cultures of inner ears
have also demonstrated a factor of the otic epithelium that chemically attracts growing SAG fibers (11).
Moreover, the number of SAG neurons was greater when the explanted otocyst was intact than when
the SAG was isolated and cultured alone (12). This observation suggests that a substance with inherent
neurotrophic properties is released by the sensory epithelium. Other coculture experiments (13) have
shown that 1. a diffusible factor, developmentally regulated, is produced by the otocyst and promotes
neurite outgrowth from SAG explants and 2. the release of this factor decreases during development,
whereas the SAG maintains its capacity to respond throughout the course of development. Therefore, in
both developing mouse and chick embryos there is a decrease of neurotropic factor released from the
otocyst during the period when SAG makes contacts with the target hair cells.

Further, during the chick inner ear development, a considerable neuronal cell death is observed in
the SAG while SAG neurons make contacts with their peripheral and central targets (14). This cell death
is dramatically augmented when natural targets are removed but it is diminished when targets are added
(12). These observations provide evidence that trophic substances are delivered by the natural targets of
SAG neurons.

The question arises, what are the trophic substances required for normal development and
survival of ganglionic neurons? Preliminary investigations concerned the well characterized
neurotrophic "nerve growth factor" (NGF). Briefly, NGF is the prototype of the family of
neurotrophins, a group of proteins sharing almost 60% amino acid identity and supporting neuronal
survival both in the developing and adult nervous system. This family includes the brain-derived
neurotrophic factor (BDNF) (15), neurotrophin 3 (NT-3) (16), and homologous neurotrophins 4 and 5
(17). NGF is able to stimulate neuronal outgrowth in sensory and sympathetic ganglia (18). NGF can
direct the outgrowth of a growth cone from embryonic sensory neurons when applied with a
micropipette (19). These chemotropic effects of NGF have also been demonstrated in
compartimentalized cultures of developing sympathetic neurons where the local NGF concentration
exerts control over neurite outgrowth (20).

These properties of NGF directed interest to its possible role in the development of inner ear
innervation. The first indication of the implication of NGF in the inner ear came from the in vivo
immunohistochemical localization of a NGF-like protein in the developing rat cochlea. The
immunostaining was restricted to hair cells from birth up to postnatal day 8 and was not observed in
spiral ganglion neurons (21). A maturation gradient of NGF-like expression was described: at birth the
staining was more intense near the basal coil, at P6-7 it was predominant at the apical coil.

In vitro experiments have reported that cultured otocyst from El2 rats, but not from later ages,
released a NGF-like substance into the culture medium that promotes the in vitro survival and
neuritogenesis of neurons of both SAG and sympathetic ganglia (22). This NGF-like activity was
suppressed by polyclonal anti-NGF antibodies. In other investigations a vigorous neurite outgrowth
was obtained in response to exogenous NGF application (23). All this evidence added together, it was
reasonable to assume that NGF or a NGF-like molecule was responsible for the development of inner
ear innervation and SAG neurons survival and maintenance. Other studies confirm this hypothesis. In
avian embryos, binding studies with 125I NGF have reported the presence of specific NGF ligands in
the cochlear portion of the SAG and in the otic epithelium (24-25).

The current idea is that NGF binding is carried out by two types of receptors namely a
transmembrane glycoprotein (gp75LNGFR or gp75) which binds NGF with a low affinity and a
transmembrane tyrosine kinase (gpl4Otrk A, gene product of the protooncogene trk) which, perhaps
1294 Neurotrophins and Cochlea Vol. 54, No. 18, 1994

in combination with gp75, binds NGF with a high affinity (26-27).

Immunohistochemistry (28-29) and in situ hybridization studies (30-31) contributed some

complementary data on the gp75 expression in the developing inner ear. It was concluded from these
data that the sensory epithelium and SAG neurons express gp75 during the first stage of inner ear
development and when peripheral ganglionic fibers enter the sensory epithelia of the auditory organ.
Later, gp75mRNA is expressed by neuronal cell bodies but gp75 protein is only detected in nerve
fibers, particularly in the intraganglionic spiral bundle.

We know from recent data that gp75 binds not only NGF but also BDNF, NT-3 and NT-4 with
low affinity (15-17). Recent in situ hybridizations (32-33) have shown that NT-3 and BDNF, rather
than others neurotrophins, are the predominant neurotrophins present in the target field of the
developing spiral ganglion of the rat. Surprisingly, in spite of the numerous above cited studies related
to NGF action in the inner ear, NGF mRNA has not yet been detected in the inner ear during
development. On the other hand, NT-3 mRNA expression started at E10-Ell in the presumptive
sensory region of the otic vesicle. Later, NT-3 mRNA was detected in sensory fields of the cochlea, as
in vestibular receptors such as the utriculus and sacculus but not into crista ampularis. Transcripts were
localized both in sensory hair cells and surrounding supporting ceils (32-33). During the perinatal
period, a gradient between the basal and apical coils of the cochlea was observed: NT-3 mRNA
expression was more intense near the immature apex than near the more developed basal coil. NT-3
expression disappeared by P7-P9. Auditory or vestibular ganglion cells never expressed NT-3 mRNA
(32). BDNF mRNA was found in sensory regions of the otocyst and cochlea from E-11 to the first
postnatal week. In the neonatal period, BDNF expression was restricted to sensory hair cells. BDNF
trancripts were not seen in SAG or spiral ganglion (32-33). Moreover Pirvola et al. (32) report that NT-
3 and BDNF but not NGF, at physiological concentrations, induced neurite outgrowth from E11-El2
SAG explants. Finally, data from prenatal guinea pigs, where spiral ganglion neurons were unaffected
by intra-uterine exposure to maternal antibodies to NGF (34), and from chicken, where the SAG was
almost unresponsive to NGF in vitro (35), are consistent with the evidence that NGF is related to the
survival of sensory neurons only derived from neural crest (36). The neurotrophins BDNF and NT-3,
however can support survival of sensory neurons both of placodal and neural crest origin (16,36-37)
and thus they are possible candidates for neurotrophic actions in SAG neurons.

Since the characterization of the two receptors for NGF, several members of the tyrosine kinase
trk family have been found to be involved in the mediation of neurotrophin biological activity, Among
them are gp145trk B and gp145trk C. These are essential components of functional high affinity
receptors for BDNF and NT3 respectively (see ref 38). It has been reported (33) that spiral and
vestibular ganglion cells express trkB and trkC mRNA but not trkA mRNA at El3 and El6. The
expression of BDNF and NT3 by sensory epithelia of auditory and vestibular organs (except crista
ampularis which expresses only BDNF) together with the presence of the high affinity receptors trkB
and trkC and the low affinity receptor gp75 for these neurolxophins in cochlear and vestibular ganglia at
the time of fiber entry and ganglionic maturation, strongly suggest that BDNF and NT3 are involved in
the development of the innervation of the inner ear end organ.

The fact that two neurotrophins are present in the sensory epithelium and their respective receptors
localized in the spiral ganglion can perhaps be related to the two types of neurons already existing in this
ganglion. Type II ganglion cells innervate specifically the outer hair cells but their origin and precise
function are not kown. Yet we suggest that one of the two neurotrophins identified during cochlear
ganglion development could be specifically responsible for T 1I cell connection and differentiation. We
may also suggest another possibility: one of the neurotrophins identified could be particulary involved
in the development of the efferent innervation of the cochlea.

Interactions between cochlea and efferent innervation

The efferent innervation of the cochlea originates in the superior olivary complex (SOC). This is
an important brainstem structure for binaural integration and sound localization. The SOC consists of
three principal nuclei and several peri-olivary cell clusters from which most efferent cochlear fibers
originate (see ref 39).

In the ferret, cochlear removal at P5 leads to a reduction in size and in number of neurons of the
lateral superior olivary complex ipsilateral to the removal and neurons of the medial nucleus of the
trapezoid body controlateral to the removal (40). The imbalance between excitatory and inhibitory
imputs under these conditions have been thought to be one reason for the death of neurons of the lateral
Vol. 54, No. 18, 1994 Neurotrophins and Cochlea 1295

superior olivary complex (41). However, no attention has been paid to a possible direct influence of
cochlear neurotrophins via retrograde axonal transport. We have reported that neurotrophins, probably
BDNF and NT3 are synthesized by cochlear sensory epithelium prenatally, neonatalty and postnatally
up to P7-P8 in the rat Although there are some discrepancies between data, developmental observations
on efferent innervation of the rodent cochlea show that olivocochlear fibers enter the cochlea already
before birth (42-44). In the rat cochlea, gp75 immunoreactivity has been localized in nerve fiber bundles
but not in cochlear ganglion neurons from El5 to P9 (29). Perinatally and postnatally, the gp75
immunostaining was related to the intraganglionic spiral bundle, which is the efferent innervation
pathway in the cochlea. Moreover, gp75 immunostaining was located in the auditory nerve and
brainstem structures such as the ventral cochlear nucleus, SOC and nucleus of the trapezoid body from
E18 to P9 5 (28-29). The presence of the low affinity receptor for the neurotrophins in these structures
at this period could be an indication for a role of neurotrophins in the maintenance and survival of SOC
neurons. Even though neurotrophins from cochlear origin could assume the survival of some brainstem
auditory neurons, spiral ganglion neurons could be dependent on neurotrophic factors originating from
their central targets and retrogradely transported.

Interactions between cochlea and its central targets

All afferents of the auditory nerve project to the cochlear nucleus which is the basis for ascending
pathways to higher levels of the central auditory system.

Little is known about neurotrophic interaction between axons of spiral ganglion cells and their
central target. Preliminary experiments by Ard et al. (12) in chick embryo inner ear cultures have
provided some hints for such interactions. SAG neurons cultured in the presence of both peripheral and
central targets showed considerably better survival as those explanted without any target. Ganglia
explanted with only the peripheral target showed the same survival than those cultured in the presence
of both central and peripheral targets. Ganglia cultured only with the central target survived better than
ganglia cultured alone suggesting that the central target produced atrophic factor for survival. In other
coculture experiments, an oriented growing and extension of SAG central processes towards the
direction of a portion of embryonic brainstem has been reported (45); this suggests that tropic
interactions may also exist between central target and SAG.

Observations on the development of embryonic or postnatal cochlear organotypic cultures (46-

47) indicate that central processes of ganglionic neurons generally disappear after few days. Spiral
ganglion neurons become monopolar. If they are maintained, axons seem to grow freely without any
apparent tendency to invade the ganglion or sensory epithelium. A directed growing of axons is
reported when the cochlear nucleus is cocultured with cochlear preparations (46). This suggests that a
central trophic influence, probably distinct from the peripheral one, is necessary for the connection of
axons of the auditory nerve with their central targets. The reports of NGF specific binding (48) and
gp75 immunoreactivity (28-29) in the cochlear nucleus may suggest that NGF or other neurotrophins
could be involved in the tropic mechanism there. However, more precise investigations are necessary to
formulate a hypothesis on central-peripheral tropic and/or trophic relations.

On the other hand, atrophic influence by cochlear axons may be exerted on central neuron
survival. Early experiments by Levi-Montalcini (49), followed by others (50-51) about effects of
cochlear removal in the chick embryo showed that the number of neurons in the cochlear nucleus
decreased dramatically. Similar observations were reported in other species such as gerbil, ferret and
mouse where it was generally observed that after postnatal cochlear removal neuron loss in the cochlear
nucleus was more severe the earlier the cochlea was removed (40,52). Yet in some other animals such
as the guinea pig, chemical destruction of the adult cochlea is followed by severe neuronal loss in the
cochlear nucleus (53). From these observations, it has been suggested that atrophic substance, released
by axon endings of the auditory nerve, could be necessary for the maintenance of primary central target
neurons. The afferent neurotransmitter, probably aspartate and/or glutamate, could be involved in such
trophic interaction (41,54) but other unknown factors should also be considered.

Conclusion
The rapid progress in the past few years concerning neurotrophic factor research, has greatly
stimulated advances in developmental biology especially in the field of neurobiology of hearing. Here,
we have summarized evidence that neurotrophins are expressed by auditory sensory epithelia during the
time at which ganglion cells with neurotrophin receptors send their processes to these epithelia. This is
the basis for neurotropic and neurotrophic interactions which results in the highly differentiated cochlear
1296 Neurotrophins and Cochlea Vol. 54, No. 18, 1994

innervation. Recent findings have led to the identification of BDNF and NT3 as responsible substances.
Since no NGF mRNA nor the NGF high affinity receptor component trkA mRNA were detectable
during the development of cochlear structures, this factor is not likely to be an important neurotrophin at
this level. The contradictory observations mentioned earlier, related to the effects of the NGF molecule
or NGF antibodies on SAG fiber outgrowth (22-23,32,35) underline once more the difficulties in the
interpretation of in vitro results. It is obvious that conclusions must be drawn with caution.

By their biological activity, neurotrophins could be responsible for chemotrophic, differentiation,

survival, and maintenance functions at the afferent as well as at the efferent level of the inner ear
development. So far we have not been able to elucidate the physiological aspect of neurotrophin
function, although their identity and location are practically known. The study of the regulation of
neurotrophin expression in the inner ear may provide some important cues for the understanding of
mechanisms involved in neuronal maintenance during normal development and aging not only in
auditory function but also in other neuronal systems. Moreover, restorative properties of neurotrophins
must also be considered in the repair of neurodegenerative processes.

A_cknowled~ement

Authors thank Dr. G/inter Ehret for critical reading of the manuscript.

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