Postnatal homozygous neurotrophin-3 mutant mice display a loss of about half the sympathetic superior cervical ganglion (SCG) neurons (Ernfors, P., Lee, K.-F., Kucera, J. and Jaenisch, R. (1994a) Cell 77, 503–512; Farinas, I., Jones, K. R., Backus, C., Wang, X. Y. and Reichardt, L. F. (1994) Nature 369, 658–661). We found that this loss is caused by excessive apoptosis of sympathetic neuroblasts leading to a failure to generate a normal number of neurons during neurogenesis. NT-3 was also found to be required postnatally. In Nt-3−/− mice, sympathetic fibers failed to invade pineal gland and external ear postnatally; whereas other targets of the external and internal carotid nerves, including the submandibular gland and the iris, displayed a normal complement of sympathetic innervation. Sympathetic fibers of mice carrying one functional copy of the Nt-3 gene (Nt-3+/− mice) invaded the pineal gland, but failed to branch and form a ground plexus. Cultured neonatal sympathetic neurons responded to NT-3 by neurite outgrowth and mRNA upregulation of the NT-3 receptor, trkC. Exogenously administered NT-3 promoted sympathetic growth and rescued the sympathetic target deficit of the mutant mice. We conclude that NT-3 is required for the survival of sympathetic neuroblasts during neurogenesis and for sympathetic innervation and branching in specific targets after birth.

Reference

Reference
Bandtlow
C. E.
,
Heumann
R.
,
Schwab
M. E.
,
Thoenen
H.
(
1987
)
Cellular localization of nerve growth factor synthesis by in situ hybridization.
EMBO J
6
,
891
899
Barde
Y.-A.
,
Edgar
D.
,
Thoenen
H.
(
1982
)
Purification of a new neurotrophic factor from mammalian brain.
EMBO J
1
,
549
553
Berkemeier
L. R.
,
Winslow
J. W.
,
Kaplan
D. R.
,
Nicolics
K.
,
Goeddel
D. V.
,
Rosenthal
A.
(
1991
)
Neurotrophin-5: A novel neurotrophic factor that activates trk and trkB.
Neuron
7
,
857
866
Birren
S. J.
,
Lo
L.
,
Anderson
D. J.
(
1993
)
Sympathetic neuroblasts undergo a developmental switch in trophic dependence.
Development
119
,
597
610
Bjerre
B.
,
Björklund
A.
,
Mobley
W.
(
1973
)
A stimulatory effect by nerve growth factor on the regrowth of adrenergic fibres in the mouse peripheral tissues after chemical sympathoectomy with 6-hydroxydopamine.
Z. Zellforsch
146
,
15
43
Cochard
P.
,
Goldstein
M.
,
Black
I. B.
(
1978
)
Ontogenetic appearance and disappearance of tyrosine hydroxylase and chatecholamines in the rat embryo.
Proc. Natl. Acad. Sci. USA
280
,
141
142
Cochard
P.
,
Goldstein
M.
,
Black
I. B.
(
1979
)
Initial development of the noradrenergic phenotype in autonomic neuroblasts of the rat embryo in vivo.
Dev. Biol
71
,
100
114
Cohen
S.
,
Levi-Montalcini
R.
,
Hamburger
V.
(
1954
)
A nerve growth-stimulating factor isolated from sarcomas 37 and 180.
Proc. Natl. Acad. Sci. USA
40
,
1014
1018
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.
,
Friedman
B.
,
Wiegand
S.
,
Vejsada
R.
,
Kato
A. C.
,
DeCjiara
T. M.
,
Yancopolous
G. D.
(
1995
)
Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT-4.
Nature
375
,
235
238
Copray
J. C. V. M.
,
Brouwer
N.
(
1994
)
Selective expression of neurotrophin-3 messenger RNA in muscel spindles of the rat.
Neurosci
63
,
1125
1135
Coughlin
M. D.
,
Collins
M. D.
(
1985
)
Nerve growth factor-independent development of embryonic mouse sympathetic neurons in dissociated culture.
Dev. Biol
110
,
392
401
Coughlin
M. D.
,
Boyer
D. B.
,
Black
I. B.
(
1977
)
Embryonic development of a mouse sympathetic ganglion in vivo and in vitro.
Proc. Natl. Acad. Sci. USA
74
,
3438
3442
Davies
A. M.
,
Bandtlow
C.
,
Heumann
R.
,
Korsching
S.
,
Rohrer
H.
,
Thoenen
H.
(
1987
)
Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor.
Nature
326
,
353
358
Davies
A. M.
,
Horton
A.
,
Burton
L. E.
,
Schmeizer
C.
,
Vandlen
R.
,
Rosenthal
A.
(
1993
)
Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons.
J. Neurosci
13
,
4961
4967
Davies
A. M.
,
Thoenen
H.
,
Barde
Y.-A.
(
1986
)
The response of chick sensory neurons to brain-derived neurotrophic factor.
J. Neurosci
6
,
1897
1904
Dechant
G.
,
Rodrigues-Tebar
A.
,
Kolbeck
R.
,
Barde
Y.-A.
(
1993
)
Specific high-affinity receptors for neurotrophin-3 on sympathetic neurons.
J. Neurosci
13
,
2610
2616
DiCicco-Bloom
E.
,
Friedman
W. J.
,
Black
I. B.
(
1993
)
NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival.
Neuron
11
,
1101
1111
Ernfors
P.
,
Persson
H.
(
1991
)
Developmentally regulated expression of HDNF/NT-3 mRNA in rat spinal cord motoneurons and detection of BDNF mRNA in embryonic dorsal root ganglion.
Eur. J. Neurosci
3
,
953
961
Ernfors
P.
,
Ibanez
C. F.
,
Ebendal
T.
,
Olson
L.
,
Persson
H.
(
1990
)
Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain.
Proc. Natl. Acad. Sci. USA
87
,
5454
5458
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.
,
Merlio
J.-P.
,
Persson
H.
(
1992
)
Cells expressing mRNA for neurotrophins and their receptors during embryonic rat development.
Eur. J. Neurosci
4
,
1140
1158
Ernfors
P.
,
Van De Water
T. R.
,
Loring
J.
,
Jaenisch
R.
(
1995
)
Complementary roles of BDNF and NT-3 in the auditory and vestibular development.
Neuron
14
,
1153
1164
Ernfors
P.
,
Wetmore
C.
,
Olson
L.
,
Persson
H.
(
1990
)
Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family.
Neuron
5
,
511
526
Ernsberger
U.
,
Edgar
D.
,
Rohrer
H.
(
1989
)
The survival of early chick sympathetic neurons in vitro is dependent on a suitable substrate but independent of NGF.
Dev. Biol
135
,
250
262
Farinas
I.
,
Jones
K. R.
,
Backus
C.
,
Wang
X. Y.
,
Reichardt
L. F.
(
1994
)
Severe sensory and sympathetic deficits in mice lacking neurotrophin-3.
Nature
369
,
658
61
Friedman
W. J.
,
Ernfors
P.
,
Persson
H.
(
1991
)
In situ hybridization reveals both transient and persistent expression of HDNF/NT-3 mRNA in the rat brain during postnatal development.
J Neurosci
11
,
1577
1584
Friedman
W. J.
,
Olson
L.
,
Persson
H.
(
1991
)
Brain-derived neurotrophic factor mRNA expressing cells in the developing postnatal brain.
Eur. J. Neurosci
63
,
43
51
Friedman
W. J.
,
Olson
L.
,
Persson
H.
(
1991
)
Temporal and spatial expression of NGF receptor mRNA during postnatal rat brain development analyzed by in situ hybridization.
Brain Res
63
,
43
51
Garner
A. S.
,
Large
T. H.
(
1994
)
Isoforms of the avian trkC receptor: A novel kinase insertion dissociates transformation and process outgrowth from survival.
Neuron
13
,
457
472
Gloster
A.
,
Diamond
J.
(
1992
)
Sympathetic nerves in adult rats regenerate normally and restore pilomotor function during an anti-NGF treatment that prevents their collateral sprouting.
J. Comp. Neurol
326
,
363
374
Hallböök
F.
,
Ibanez
C. F.
,
Persson
H.
(
1991
)
Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary.
Neuron
6
,
1
20
Heumann
R.
,
Korsching
S.
,
Scott
J.
,
Thoenen
H.
(
1984
)
Relationshipbetween levels of nerve growth factor and its messenger RNA in sympathetic ganglia and peripheral target tissues.
EMBO J
3
,
3183
3189
Hohn
A.
,
Leibrock
J.
,
Bailey
K.
,
Barde
Y. A.
(
1990
)
Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family.
Nature
344
,
339
341
Hory-Lee
F.
,
Russel
M.
,
Lindsay
R. M.
,
Frank
E.
(
1993
)
Neurotrophin-3 supports the survival of developing muscle sensory neurons in culture.
Proc. Natl. Acad. Sci. USA
90
,
2613
2617
Ip
N.
,
Ibanez
C.
,
Nye
S.
,
McClain
J.
,
Jones
P.
,
Gies
D.
,
Belluscio
L.
,
Le Beu
M.
,
Espinosa III
M.
,
Squinto
R.
,
Persson
H.
,
Yancopolous
G.
(
1992
)
Mammalian neurotrophin-4: Structure, distribution and receptor specificity.
Proc. Natl. Acad. Sci. USA
89
,
3060
3064
Jones
K.
,
Reichardt
L.
(
1990
)
Molecular cloning of a human gene that is a member of the nerve growth factor family.
Proc. Natl. Acad. Sci. USA
87
,
8060
8064
Kaisho
Y.
,
Yoshimura
K.
,
Nakahama
K.
(
1990
)
Cloning and expression of a cDNA encoding a novel human neurotrophic factor.
FEBS Lett
266
,
187
191
Landis
S. C.
,
Schwab
M.
,
Siegel
R. E.
(
1988
)
Evidence for neurotransmitter plasticity in vivo: II. immunocytochemical studies of rat sweat gland innervation during development.
Dev. Biol
126
,
129
138
Leblanc
G.
,
Landis
S. C.
(
1986
)
Development of choline acetyltransferase activity in the cholinergic sympathetic innervation of sweat glands.
J. Neurosci
6
,
260
265
Leibrock
J.
,
Lottspeich
F.
,
Hohn
A.
,
Hofer
M.
,
Hengerer
B.
,
Masiakowski
P.
,
Thoenen
H.
,
Barde
Y. A.
(
1989
)
Molecular cloning and expression of brain-derived neurotrophic factor.
Nature
341
,
149
152
Levi-Montalcini
R.
(
1987
)
The nerve growth factor 35 years later.
Science
237
,
1154
1162
Levi-Montalcini
R.
,
Angeletti
P. U.
(
1968
)
Nerve growth factor.
Physiol. Rev
48
,
534
569
Levi-Montalcini
R.
,
Booker
B.
(
1960
)
Excessive growth of the sympathetic ganglia evoked by a protein isolated from mouse salivary glands.
Proc. Natl. Acad. Sci. USA
46
,
373
383
Lewin
G. R.
,
Mendell
L. M.
(
1993
)
Nerve growth factor and nociception.
Trends Neurosci
19
,
353
359
Lindsay
R. M.
,
Thoenen
H.
,
Barde
Y. A.
(
1985
)
Placode and neural crest derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor.
Dev. Biol
112
,
319
328
Lingappa
J. R.
,
Zigmond
R. E.
(
1987
)
Pineal transplants in oculo: limitations on the ability of collateral sprouts of foreign neurons to establish normal function.
J. Neurosci
7
,
3225
3228
Liu
X.
,
Ernfors
P.
,
Wu
H.
,
Jaenisch
R.
(
1995
)
Sensory but not motor neuron deficits in mie lacking NT-4 and BDNF.
Nature
375
,
238
240
Maisonpierre
P. C.
,
Belluscio
L.
,
Friedman
B.
,
Alderson
R. F. J. W. S.
,
Furth
M. E.
,
Lindsay
R. M. D. Y. G.
(
1990
)
NT-3, BDNF and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression.
Neuron
5
,
501
509
Maisonpierre
P. C.
,
Belluscio
L.
,
Squinto
S.
,
Ip
N. Y.
,
Furth
M. E.
,
Lindsay
R. M.
,
Yancopolous
G. D.
(
1990
)
Neurotrophin-3: A neurotrophic factor related to NGF and BDNF.
Science
247
,
1446
1451
Merlio
J.-P.
,
Ernfors
P.
,
Jaber
M.
,
Persson
H.
(
1992
)
Molecular cloning of rat trkC and identification of cells expressing mRNAs for members of the trk family in the rat central nervous system.
Neuroscience
51
,
513
532
Olson
L.
(
1967
)
Outgrowth of sympathetic adrenergic neurons in mice treated with nerve growth factor.
Z. Zellforsch. Mikrosk. Anat
81
,
155
173
Phillips
H. S.
,
Hains
J. M.
,
Laramee
G. R.
,
Rosenthal
A.
,
Winslow
J. W.
(
1990
)
Widespread expression of BDNF but not NT-3 by target areas of basal forebrain cholinergic neurons.
Science
250
,
290
294
Pirvola
U.
,
Ylikoski
J.
,
Palgi
J.
,
Lethonen
E.
,
Arumäe
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
Purves
D.
,
Snider
W. D.
,
Voyvodic
J. T.
(
1988
)
Trophic regulation of nerve cell morphology and innervation in the autonomic nervous system.
Nature
336
,
123
128
Rohrer
H.
,
Thoenen
H.
(
1987
)
Relationship between differentiation and terminal mitosis: chick sensory and ciliary neurons differentiate after terminal mitosis of precursor cells, whereas sympathetic neurons continue to divide after differentiation.
J. Neurosci
7
,
3739
3748
Rosenthal
A. V. G. D.,
,
Nguyen
T.
,
Lewis
M.
,
Shih
A.
,
Laramee
G. R.
,
Nikolics
K.
,
Winslow
J. W.
(
1990
)
Primary structure and biological activity of a novel human neurotrophic factor.
Neuron
4
,
767
773
Rothman
T. P.
,
Gershon
M. D.
,
Holtzer
H.
(
1978
)
The relationship of cell division to the acquisition of adrenergic characteristics by developing sympathetic ganglion cell precursors.
Dev. Biol
65
,
322
341
Rothman
T. P.
,
Specht
L. A.
,
Gershon
M. D.
,
John
T. H.
,
Teitelman
G.
,
Pickel
V. M.
,
Reis
D. J.
(
1980
)
Catecholamine biosynthetic enzymes are expressed in replicating cells of the peripheral but not the central nervous system.
Proc. Natl. Acad. Sci. USA
77
,
6221
6225
Schecterson
L. C.
,
Bothwell
M.
(
1992
)
Novel roles for neurotrophins are suggested by BDNF and NT3 mRNA expression in developing neurons.
Neuron
9
,
449
463
Shelton
D.
,
Reichardt
L.
(
1984
)
Studies on regulation of beta-nerve growth factor gene expression in the rat iris. The level of mRNA encoding nerve growth factor is increased in irises placed in explant cultures in vitro, but not in irises deprived of sensory or sympathetic innervation in vivo.
J. Cell. Biol
102
,
1940
1948
Shelton
D. J.
,
Reichardt
L. F.
(
1984
)
Expression of the nerve growth factor gene correlates with the density of sympathetic innervation in effector organs.
Proc. Natl. Acad. Sci. USA
81
,
7951
7955
Torre
D. L.
(
1980
)
An improved approach to histofuorescence using the SPG method for tissue monoamines.
J. Neurosci. Meth
3
,
1
5
Tsoulfas
P.
,
soppet
D.
,
Escandon
E.
,
Tessarollo
L.
,
Mendoza-Ramirez
J.-L.
,
Rosenthal
A.
,
Nikolics
K.
,
Parada
L. F.
(
1993
)
The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells.
Neuron
10
,
975
990
Valenzuela
D. M.
,
Maisonpierre
P. C.
,
Glass
D. J.
,
Rojas
E.
,
Nunez
L.
,
Kong
Y.
,
Gies
D. R.
,
Stitt
T. N.
,
Ip
N. Y.
,
Yancopolous
G. D.
(
1993
)
Alternative forms of rat trkC with different functional capabilities.
Neuron
10
,
963
974
Verdi
J. M.
,
Anderson
D. J.
(
1994
)
Neurotrophins regulate sequential changes in neurotrophin receptor expression by sympathetic neuroblasts.
Neuron
13
,
1359
1372
Wright
L. L.
,
Cunningham
T. J.
,
Smolen
A. J.
(
1983
)
Developmental neuronal death in the rat superior cervical ganglion: cell counts and ultrastructure.
J. Neurocyt
12
,
727
738
This content is only available via PDF.