The generation of mice lacking specific neurotrophins permits evaluation of the trophic requirements of particular neuronal populations throughout development. In the present study, we examined the developing vestibulocochlear system to determine the time course of neurotrophin dependence and to determine whether competition occurred among developing cochlear or vestibular neurons for available amounts of either brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5). Both cochlear and vestibular neurons were present in mice lacking NT-4/5. In contrast, vestibular neurons decreased in number beginning at mid-stages of inner ear development, in mice lacking BDNF. Early in development (E12.5-13), the size of the vestibular ganglion was normal in bdnf −/− mice. Decreased innervation to vestibular sensory epithelia was detected at E13.5-15, when progressive loss of all afferent innervation to the semicircular canals and reduced innervation to the utricle and saccule were observed. At E16.5-17, there was a reduction in the number of vestibular neurons in bdnf −/− mice. A further decrease in vestibular neurons was observed at P1 and P15. Compared to bdnf −/− mice, mice heterozygous for the BDNF null mutation (bdnf +/−) showed an intermediate decrease in the number of vestibular neurons from E16.5-P15. These data indicate a late developmental requirement of vestibular neurons for BDNF and suggest competition among these neurons for limited supplies of this factor.

Reference

Abercrombie
M.
(
1946
)
Estimation of nuclear population from microtome sections.
Anat. Rec
94
,
239
247
Acheson
A.
,
Conover
J. C.
,
Fandl
J. P.
,
DeChiara
T. M.
,
Russell
M.
,
Thadani
A.
,
Squinto
S. P.
,
Yancopoulos
G. D.
,
Lindsay
R. M.
(
1995
)
A BDNF autocrine loop in adult sensory neurons prevents cell death.
Nature
374
,
450
453
Alvarez
I. S.
,
Navascues
J.
(
1990
)
Shaping, invagination, and closure of the chick embryo otic vesicle: Scanning electron microscopic and quantitative study.
Anat. Rec
228
,
315
326
Avila
M. A.
,
Varela-Nieto
I.
,
Romero
G.
,
Mato
J. M.
,
Giraldez
F.
,
Van De Water
T. R.
,
Represa
J.
(
1993
)
Brain-derived neurotrophic factor and neurotrophin-3 support the survival and neuritogenesis response of developing cochleovestibular ganglion neurons.
Dev. Biol
159
,
266
275
Berglund
A. M.
,
Ryugo
D. K.
(
1986
)
A monoclonal antibody labels type II neurons of the spiral ganglion.
Hear. Res
383
,
327
332
Bianchi
L. M.
,
Cohan
C. S.
(
1993
)
The effects of neurotrophins and CNTF on developing statoacoustic neurons: Comparison with an otocyst-derived factor.
Dev. Biol
159
,
353
365
Conover
J. C.
,
Erickson
J. T.
,
Katz
D. M.
,
Bianchi
L. M.
,
Poueymirou
W. T.
,
McClain
J.
,
Pan
L.
,
Helgren
M.
,
Ip
N. Y.
,
Boland
P.
,
Freidman
B.
,
Weigand
S.
,
Vejsada
R.
,
Kato
A.
,
DeChiara
T. M.
,
Yancopoulos
G. D.
(
1995
)
Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT-4.
Nature
375
,
235
238
Corwin
J. T.
,
Cotanche
D. A.
(
1989
)
Development of location-specific hair cell stereocilia in denervated embryonic ears.
J. Comp. Neurol
288
,
529
537
Crowley
C.
,
Spencer
S. D.
,
Nishimura
M. C.
,
Chen
K. S.
,
Pitts-Meek
S.
,
Armani
M. P.
,
Ling
L. H.
,
McMahon
S. B.
,
Shelton
D. L.
,
Levinson
A. D.
,
Phillips
H. S.
(
1994
)
Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons.
Cell
76
,
1001
1011
Davies
A.
,
Thoenen
H.
,
Barde
Y.-A.
(
1986
)
The response of chick sensory neurons to brain-derived neurotrophic factor.
J. Neurosci
6
,
1897
1904
Davies
A.
(
1988
)
Role of neurotrophic factors in development.
Trends in Genet
4
,
139
143
Dechant
G.
,
Biffo
S.
,
Okazawa
H.
,
Kolbeck
R.
,
Pottgiesser
J.
,
Barde
Y.-A.
(
1993
)
Expression and binding characteristics of the BDNF receptor chick TrkB.
Development
119
,
545
558
Desmadryl
G.
,
Sans
A.
(
1990
)
Afferent innervation in crista ampullaris of the mouse during ontogenesis.
Dev. Brain Res
52
,
183
189
Ernfors
P.
,
Lee
K.-F.
,
Jaenisch
R.
(
1994
)
Mice lacking brain-derived neurotrophic factor develop with sensory deficits.
Nature
368
,
147
150
Ernfors
P.
,
Lee
K.-F.
,
Kucera
J.
,
Jaenisch
R.
(
1994
)
Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents.
Cell
77
,
503
512
Ernfors
P.
,
Van De Water
T.
,
Loring
J.
,
Jaenisch
R.
(
1995
)
Complementary roles of BDNF and NT3 in vestibular and auditory development.
Neuron
14
,
1153
1164
Farinas
I.
,
Jones
K. R.
,
Backus
C.
,
Wanf
X.-Y.
,
Reichardt
L. F.
(
1994
)
Severe sensory and sympathetic deficits in mice lacking neurotrophin-3.
Nature
369
,
658
661
Fritzsch
B.
,
Nichols
D. H.
(
1993
)
DiI reveals a prenatal arrival of efferents at the differentiating otocyst of mice.
Hear. Res
65
,
51
60
Hallböök
F.
,
Ibáñez
C. F.
,
Ebendal
T.
,
Persson
H.
(
1993
)
Cellular localization of brain-derived neurotrophic factor and neurotrophin-3 mRNA expression in the early chicken embryo.
Eur. J. Neurosci
5
,
1
14
Hollyday
M.
,
Hamburger
V.
(
1976
)
Reduction of the naturally occurring motor neuron loss by enlargement of the periphery.
J. Comp. Neurol
170
,
311
320
Jones
K. R.
,
Farinas
I.
,
Backus
C.
,
Reichardt
L. F.
(
1994
)
Targeteddisruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development.
Cell
76
,
989
999
Knowlton
V. Y.
(
1967
)
Correlation of the development of membranous and bony labyrinths, acoustic ganglia, nerves and brain centers of the chick embryo.
J. Morph
121
,
179
208
Lefebvre
P. P.
,
Van De Water
T. R.
,
Weber
T.
,
Rogister
B.
,
Moonen
G.
(
1991
)
Growth factor interactions in cultures of dissociated adult acoustic ganglia: neuronotrophic effects.
Brain Res
567
,
306
312
Levi-Montalcini
R.
,
Booker
B.
(
1960
)
Destruction of the sympathetic ganglia in mammals by antiserum to a nerve growth factor protein.
Proc. Natl. Acad. Sci. USA
46
,
384
391
Levi-Montalcini
R.
,
Angeletti
P. U.
(
1966
)
Immunosympathectomy.
Pharmacol. Rev
10
,
619
628
Levi-Montalcini
R.
(
1987
)
The nerve growth factor 35 years later.
Science
237
,
1154
1162
Li
C. W.
,
Van De Water
T. R.
,
Ruben
R. J.
(
1978
)
The fate mapping of the eleventh and twelfth day mouse otocyst: An in vitro study of the sites of orgin of the embryonic inner ear sensory structures.
J. Morph
157
,
249
268
Lindsay
R. M.
,
Wiegand
S. J.
,
Altar
C. A.
,
DiStefano
P. S.
(
1994
)
Neurotrophic factors: from molecule to man.
Trends Neurosci
17
,
182
190
Liu
X.
,
Ernfors
P.
,
Wu
H.
,
Jaenisch
R.
(
1995
)
Sensory but not motor neuron deficits in mice lacking NT4 and BDNF.
Nature
375
,
238
240
Mbiene
J. P.
,
Favre
D.
,
Sans
A.
(
1988
)
Early innervation and differentiation of hair cells in the vestibular epithelia of mouse embryos: SEM and TEM study.
Anat. Embryol
177
,
331
340
Pirvola
U.
,
Ylikoski
J.
,
Palgi
J.
,
Lehtonen
E.
,
Arumae
U.
,
Saarma
M.
(
1992
)
Brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the peripheral target fields of developing inner ear ganglia.
Proc. Natl. Acad. Sci. USA
89
,
9915
9919
Pirvola
U.
,
Arumae
U.
,
Moshnyakov
M.
,
Palgi
J.
,
Saarma
M.
,
Ylikoski
J.
(
1994
)
Coordinated expression and function of neurotrophins and their receptors in the rat inner ear during target innervation.
Hear. Res
75
,
131
144
Represa
J.
,
Bernd
P.
(
1989
)
Nerve growth factor and serum differentially regulate development of embryonic otic vesicle and cochleovestibular ganglion in vitro.
Dev. Biol
134
,
21
29
Schecterson
L.
,
Bothwell
M.
(
1992
)
Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons.
Neuron
9
,
449
463
Schimmang
T.
,
Minichiello
L.
,
Vazquez
E.
,
San Jose
I.
,
Giraldez
F.
,
Klein
R.
,
Represa
J.
(
1995
)
Developing inner ear sensory neurons require Trk B and Trk C receptors for innervation of their peripheral targets.
Development
121
,
3381
3391
Swanson
G. J.
,
Howard
M.
,
Lewis
J.
(
1990
)
Epithelial autonomy in the development of the inner ear of a bird embryo.
Dev. Biol
137
,
243
257
Vogel
K. S.
,
Davies
A. M.
(
1991
)
The duration of neurotrophic factor independence in early sensory neurons is matched to the time course of target field innervation.
Neuron
7
,
819
830
Wheeler
E. F.
,
Bothwell
M.
,
Schecterson
L. C.
,
von Bartheld
C. S.
(
1994
)
Expression of BDNF and NT3 mRNA in hair cells of the organ of Corti: Quantitative analysis in developing rats.
Hear. Res
73
,
46
56
Ylikoski
J.
,
Pirvola
U.
,
Moshnyakov
M.
,
Palgi
J.
,
Arumae
U.
,
Saarma
M.
(
1993
)
Expression patterns of neurotrophin and their receptor mRNAs in the rat inner ear.
Hear. Res
65
,
69
78
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