Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are members of the transforming growth factor-beta family and have been shown to elicit neurotrophic effects upon several classes of neurons including dopaminergic neurons, motoneurons, parasympathetic, sympathetic as well as primary sensory neurons. However, there is little information available on their roles in cutaneous innervation. Herein, we have studied the regulation of gdnf, ntn and the GDNF family receptors and examined their role in the development of facial cutaneous innervation in GDNF mutant mice. A dynamic spatial and temporal regulation of gdnf, ntn and their ligand binding receptors within the follicle-sinus complex correlate with development of distinct subclasses of sensory nerve endings. Furthermore, development of NGF-dependent myelinated mechanoreceptors, i.e. reticular and transverse lanceolate endings also require GDNF during ending formation and maintenance. In addition, ligand and receptor association seems to be intricately linked to a local Schwann cell-axon interaction essential for sensory terminal formation. Our results suggests that functionally specified nerve endings depend on different GDNF family members and that in contrast to neurotrophins, this family of neurotrophic factors may be acting at local sites of terminal Schwann cell-axon growth cone interactions and that they collaborate with neurotrophins by supporting the same populations of neurons but at different times in development.

Reference

Airaksinen
M. S.
,
Koltzenburg
M.
,
Lewin
G. R.
,
Masu
Y.
,
Helbig
C.
,
Wolf
E.
,
Brem
G.
,
Toyka
K. U.
,
Thoenen
H.
,
Meyer
M.
(
1996
)
Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation.
Neuron
16
,
287
295
Anderson
R. G.
(
1993
)
Plasmalemmal caveolae and GPI-anchored membrane proteins.
Curr. Opin. Neurobiol
5
,
647
652
Baloh
R. H.
,
Gorodinsky
A.
,
Golden
J. P.
,
Tansey
M. G.
,
Keck
C. L.
,
Popescu
N. C.
,
Johnson
E. M.
,
Milbrandt
J.
(
1998
)
Gfr-alpha-3 is an orphan member of the gdnf/neurturin/persephin receptor family.
Proc. Natl. Acad. Sci. USA
95
,
5801
5806
Baloh
R. H.
,
Tansey
M. G.
,
Golden
J. P.
,
Creedon
D. J.
,
Heuckeroth
R. O.
,
Keck
C. L.
,
Zimonjic
D. B.
,
Popescu
N. C.
,
Johnson
E. M.
Jr.
,
Milbrandt
J.
(
1997
)
TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret.
Neuron
18
,
793
802
Baloh
R. H.
,
Transey
M. G.
,
Lampe
P. A.
,
Fahrner
T. J.
,
Enomoto
H.
,
Simburger
K. S.
,
Leitner
M. L.
,
Araki
T.
,
Johnson
E. M.
,
Milbrandt
J.
(
1998
)
Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFR3-RET receptor complex.
Neuron
21
,
1291
1302
Bennett
D. L.
,
Michael
G. J.
,
Ramachandran
N.
,
Munson
J. B.
,
Averill
S.
,
Yan
Q.
,
McMahon
S. B.
,
Priestley
J. V.
(
1998
)
A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury.
J. Neurosci
18
,
3059
3072
Brown
D.
,
Rose
K.
(
1992
)
Sorting of GPI-anchored proteins to glucolipid enriched membrane subdomains during transport to the apical surface.
Cell
68
,
533
544
Buj-Bello
A.
,
Adu
J.
,
Pinon
L. G.
,
Horton
A.
,
Thompson
J.
,
Rosenthal
A.
,
Chinchetru
M.
,
Buchman
V. L.
,
Davies
A. M.
(
1997
)
Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase.
Nature
387
,
721
724
Buj-Bello
A.
,
Buchman
V. L.
,
Horton
A.
,
Rosenthal
A.
,
Davies
A. M.
(
1995
)
GDNF is an age-specific survival factor for sensory and autonomic neurons.
Neuron
15
,
821
828
Buttiglione
M.
,
Revest
J. M.
,
Rougon
G.
,
Faivre-Sarrailh
C.
(
1996
)
F3 neuronal adhesion molecule controls outgrowth and fasciculation of cerebellar granule cell neurites: A cell-type specific effect mediated by Ig-like domains.
Mol. Cell. Neurosci
8
,
53
69
Creedon
D. J.
,
Tansey
M. G.
,
Baloh
R. H.
,
Osborne
P. A.
,
Lampe
P. A.
,
Fahrner
T. J.
,
Heuckeroth
R. O.
,
Milbrandt
J.
,
Johnson
E. M.
Jr
(
1997
)
Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons.
Proc. Natl. Acad. Sci. USA
94
,
7018
7023
Davies
A. M.
,
Lumsden
A.
(
1984
)
Relation of target encounter and neuronal death to nerve growth factor responsiveness in the developing mouse trigeminal ganglion.
J. Comp. Neurol
223
,
124
137
Dotti
C.
,
Parton
G.
,
Simmons
K.
(
1991
)
Polarized sorting of glypiated proteins in hippocampal neurons.
Nature
349
,
158
161
Durbeck
P.
,
Gennarini
G.
,
Buttiglione
M.
,
Gomez
S.
,
Rougon
G.
(
1994
)
Different domains of the F3 neuronal adhesion molecule are involved in adhesion and neurite outgrowth promotion.
Eur. J. Neurosci
6
,
461
472
Durbeck
P.
,
Gennarini
G.
,
Goridis
C.
,
Rougon
G.
(
1992
)
A soluble form of F3 neuronal cell adhesion molecule promotes neurite outgrowth.
J. Cell Biol
117
,
877
887
Enokido
Y.
,
Desauvage
F.
,
Hongo
J. A.
,
Ninkina
N.
,
Rosenthal
A.
,
Buchman
V. L.
,
Davies
A. M.
(
1998
)
Gfr-alpha-4 and the tyrosine kinase ret form a functional receptor complex for persephin.
Curr. Biol
8
,
1019
1022
Faivre-Sarrailh
C.
,
Rougon
G.
(
1997
)
Axonal molecules of the immunoglobulin superfamily bearing a GPI anchor: their role in controling neurite outgrowth.
Mol. Cell. Neurosci
9
,
109
115
Fundin
B.
,
Rice
F. L.
,
Pfaller
K.
,
Arvidsson
J.
(
1994
)
The innervation of the mystacial pad in the adult rat studied by anterograde transport of HRP-conjugates.
J. Comp. Neurol
99
,
223
246
Fundin
B. T.
,
Arvidsson
J.
,
Aldskogius
H.
,
Johansson
O.
,
Rice
S. N.
,
Rice
F. L.
(
1997
)
Comprehensive immunofluorescence and lectin binding analysis of intervibrissal fur innervation in the mystacial pad of the rat.
J. Comp. Neurol
385
,
185
206
Fundin
B. T.
,
Silos-Santiago
I.
,
Ernfors
P.
,
Fagan
A. M.
,
Aldskogius
H.
,
DeChiara
T. M.
,
Phillips
H. S.
,
Barbacid
M.
,
Yancopoulos
G. D.
,
Rice
F. L.
(
1997
)
Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR.
Dev. Biol
190
,
94
116
Granholm
A. C.
,
Srivastava
N.
,
Mott
J. L.
,
Henry
S.
,
Henry
M.
,
Westphal
H.
,
Pichel
J. G.
,
Shen
L.
,
Hoffer
B. J.
(
1997
)
Morphological alterations in the peripheral and central nervous systems of mice lacking glial cell line-derived neurotrophic factor (GDNF): immunohistochemical studies.
J. Neurosci
17
,
1168
1178
Hellmich
H. L.
,
Kos
L.
,
Cho
E. S.
,
Mahon
K. A.
,
Zimmer
A.
(
1996
)
Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions.
Mech. Dev
54
,
95
105
Iwamoto
T.
,
Taniguchi
M.
,
Asai
N.
,
Ohkusu
K.
,
Nakashima
I.
,
Takahashi
M.
(
1993
)
cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily.
Oncogene
8
,
1087
1091
Jing
S.
,
Wen
D.
,
Yu
Y.
,
Holst
P. L.
,
Luo
Y.
,
Fang
M.
,
Tamir
R.
,
Antonio
L.
,
Hu
Z.
,
Cupples
R.
, et al. 
(
1996
)
GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
Cell
85
,
1113
24
Jing
S.
,
Yu
Y.
,
Fang
M.
,
Hu
Z.
,
Holst
P. L.
,
Boone
T.
,
Delaney
J.
,
Schultz
H.
,
Zhou
R.
,
Fox
G. M.
(
1997
)
GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family.
J. Biol. Chem
272
,
33111
33117
Klein
R. D.
,
Sherman
D.
,
Ho
W. H.
,
Stone
D.
,
Bennett
G. L.
,
Moffat
B.
,
Vandlen
R.
,
Simmons
L.
,
Gu
Q.
,
Hongo
J. A.
, et al. 
(
1997
)
A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
Nature
387
,
717
21
Kotzbauer
P. T.
,
Lampe
P. A.
,
Heuckeroth
R. O.
,
Golden
J. P.
,
Creedon
D. J.
,
Johnson
E. M.
Jr.
,
Milbrandt
J.
(
1996
)
Neurturin, a relative of glial-cell-line-derived neurotrophic factor.
Nature
384
,
467
70
Leclere
P.
,
Ekstrom
P.
,
Edstrom
A.
,
Priestley
J.
,
Averill
S.
,
Tonge
D. A.
(
1998
)
Effects of glial cell line-derived neurotrophic factor on axonal growth and apoptosis in adult mammalian sensory neurons in vitro.
Neuroscience
82
,
545
558
Lin
L. F.
,
Doherty
D. H.
,
Lile
J. D.
,
Bektesh
S.
,
Collins
F.
(
1993
)
GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.
Science
260
,
1130
1132
Lisanti
M.
,
Rodriguez-Boulan
E.
(
1990
)
Glucophospholipid membrane anchoring provides clues to the mechanism of protein sorting in polarized epithelial cells.
Trends Biochem. Sci
15
,
113
118
Masure
S.
,
Cik
M.
,
Pangalos
M. N.
,
Bonaventure
P.
,
Verhasselt
P.
,
Lesage
A. S.
,
Leysen
J. E.
,
Gordon
R. D.
(
1998
)
Molecular cloning, expression and tissue distribution of glial-cell-line-derived neurotrophic factor family receptor alpha-3 (GFRalpha-3).
Eur. J. Biochem
251
,
622
630
Milbrandt
J.
,
de Sauvage
F. J.
,
Fahrner
T. J.
,
Baloh
R. H.
,
Leitner
M. L.
,
Tansey
M. G.
,
Lampe
P. A.
,
Heuckeroth
R. O.
,
Kotzbauer
P. T.
,
Simburger
K. S.
, et al. 
(
1998
)
Persephin, a novel neurotrophic factor related to GDNF and neurturin.
Neuron
20
,
245
253
Molliver
D. C.
,
Wright
D. E.
,
Leitner
M. L.
,
Parsadanian
A. S.
,
Doster
K.
,
Wen
D.
,
Yan
Q.
,
Snider
W. D.
(
1997
)
IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.
Neuron
19
,
849
861
Moore
M. W.
,
Klein
R. D.
,
Farinas
I.
,
Sauer
H.
,
Armanini
M.
,
Phillips
H.
,
Reichardt
L. F.
,
Ryan
A. M.
,
Carver-Moore
K.
,
Rosenthal
A.
(
1996
)
Renal and neuronal abnormalities in mice lacking GDNF.
Nature
382
,
76
79
Naveilhan
P.
,
Baudet
C.
,
Mikaels
A.
,
Shen
L.
,
Westphal
H.
,
Ernfors
P.
(
1998
)
Expression and regulation of GFRalpha3, a glial cell line-derived neurotrophic factor family receptor.
Proc. Natl. Acad. Sci. USA
95
,
1295
300
Naveilhan
P.
,
ElShamy
W. M.
,
Ernfors
P.
(
1997
)
Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse.
Eur. J. Neurosci
9
,
1450
1460
Nosrat
C. A.
,
Tomac
A.
,
Hoffer
B. J.
,
Olson
L.
(
1997
)
Cellular and developmental patterns of expression of Ret and glial cell line-derived neurotrophic factor receptor alpha mRNAs.
Exp. Brain Res
115
,
410
422
Nosrat
C. A.
,
Tomac
A.
,
Lindqvist
E.
,
Lindskog
S.
,
Humpel
C.
,
Stromberg
I.
,
Ebendal
T.
,
Hoffer
B. J.
,
Olson
L.
(
1996
)
Cellular expression of GDNF mRNA suggests multiple functions inside and outside the nervous system.
Cell Tissue Res
286
,
191
207
Pichel
J. G.
,
Shen
L.
,
Sheng
H. Z.
,
Granholm
A. C.
,
Drago
J.
,
Grinberg
A.
,
Lee
E. J.
,
Huang
S. P.
,
Saarma
M.
,
Hoffer
B. J.
, et al. 
(
1996
)
Defects in enteric innervation and kidney development in mice lacking GDNF.
Nature
382
,
73
76
Rice
F. L.
,
Fundin
B. T.
,
Arvidsson
J.
,
Aldskogius
H.
,
Johansson
O.
(
1997
)
Comprehensive immunofluorescence and lectin binding analysis of vibrissal follicle sinus complex innervation in the mystacial pad of the rat.
J. Comp. Neurol
385
,
149
184
Rice
F. L.
,
Kinnman
E.
,
Aldskogius
H.
,
Johansson
O.
,
Arvidson
J.
(
1993
).
The innervation of the mystacial pad of the rat as revealed by PGP 9.5 immunofluorescence.
J. Comp. Neurol
337
,
366
385
Sanchez
M. P.
,
Silos-Santiago
I.
,
Frisen
J.
,
He
B.
,
Lira
S. A.
,
Barbacid
M.
(
1996
)
Renal agenesis and the absence of enteric neurons in mice lacking GDNF.
Nature
382
,
70
73
Sanicola
M.
,
Hession
C.
,
Worley
D.
,
Carmillo
P.
,
Ehrenfels
C.
,
Walus
L.
,
Robinson
S.
,
Jaworski
G.
,
Wei
H.
,
Tizard
R.
, et al. 
(
1997
)
Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins.
Proc. Natl. Acad. Sci. USA
94
,
6238
6243
Sariola
H.
,
Sainio
K.
(
1997
)
The tip-top branching ureter.
Curr. Opin. Cell Biol
9
,
877
884
Son
Y. J.
,
Thompson
W. J.
(
1995
)
Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells.
Neuron
14
,
133
141
Son
Y. J.
,
Thompson
W. J.
(
1995
)
Schwann cell processes guide regeneration of peripheral axons.
Neuron
14
,
125
132
Suvanto
P.
,
Hiltunen
J. O.
,
Arumae
U.
,
Moshnyakov
M.
,
Sariola
H.
,
Sainio
K.
,
Saarma
M.
(
1996
)
Localization of glial cell line-derived neurotrophic factor (GDNF) mRNA in embryonic rat by in situ hybridization.
Eur. J. Neurosci
8
,
816
822
Thompson
J.
,
Doxakis
E.
,
Pinon
L. G. P.
,
Strachan
P.
,
Bujbello
A.
,
Wyatt
S.
,
Buchman
V. L.
,
Davies
A. M.
(
1998
)
Gfr-Alpha-4, a new Gdnf family receptor.
Mol. Cell. Neurosci
11
,
117
126
Treanor
J. J.
,
Goodman
L.
,
de Sauvage
F.
,
Stone
D. M.
,
Poulsen
K. T.
,
Beck
C. D.
,
Gray
C.
,
Armanini
M. P.
,
Pollock
R. A.
,
Hefti
F.
, et al. 
(
1996
)
Characterization of a multicomponent receptor for GDNF.
Nature
382
,
80
83
Trupp
M.
,
Arenas
E.
,
Fainzilber
M.
,
Nilsson
A. S.
,
Sieber
B. A.
,
Grigoriou
M.
,
Kilkenny
C.
,
Salazar-Grueso
E.
,
Pachnis
V.
,
Arumae
U.
(
1996
)
Functional receptor for GDNF encoded by the c-ret proto-oncogene.
Nature
381
,
785
788
Trupp
M.
,
Raynoschek
C.
,
Belluardo
N.
,
Ibanez
C. F.
(
1998
)
Multiple Gpi-anchored receptors control Gdnf-dependent and independent activation of the c-Ret receptor tyrosine kinase.
Mol. Cell. Neurosci
11
,
47
63
Trupp
M.
,
Ryden
M.
,
Jornvall
H.
,
Funakoshi
H.
,
Timmusk
T.
,
Arenas
E.
,
Ibanez
C. F.
(
1995
)
Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons.
J. Cell Biol
130
,
137
48
Widenfalk
J.
,
Tomac
A.
,
Lindqvist
E.
,
Hoffer
B.
,
Olson
L.
(
1998
)
Gfr-Alpha-3, a protein related to Gfr-Alpha-1, is expressed in developing peripheral neurons and ensheathing cells.
Eur. J. Neurosci
10
,
1508
1517
Worby
C. A.
,
Vega
Q. C.
,
Chao
H. H.
,
Seasholtz
A. F.
,
Thompson
R. C.
,
Dixon
J. E.
(
1998
)
Identification and characterization of GFRalpha-3, a novel Co-receptor belonging to the glial cell line-derived neurotrophic receptor family.
J. Biol. Chem
273
,
3502
3508
Yu
T.
,
Scully
S.
,
Yu
Y.
,
Fox
G. M.
,
Jing
S.
,
Zhou
R.
(
1998
)
Expression of GDNF family receptor components during development: Implications in the mechanisms of interaction.
J. Neurosci
18
,
4684
4696
This content is only available via PDF.