The zinc finger transcription factor gene Krox-20 is expressed in Schwann cells and is required for the myelination of peripheral nerves. We show that the regulation of Krox-20 expression in peripheral glial cells reveals three important steps in the development and differentiation of these cells. (i) Expression of Krox-20 in Schwann cells requires continuous neuronal signalling via direct axonal contact. Therefore Krox-20 appears to be a key component of the transduction cascade linking axonal signalling to myelination. (ii) Krox-20 inducibility is acquired by Schwann cells at the time that they are formed from their precursors. Diffusible factor(s) synthesised by the neural tube can mediate this transition and can be mimicked by NDFbeta or a combination of CNTF and bFGF. Furthermore, the neural tube activity is blocked by a hybrid protein containing the NDF-binding domain of the ErbB4 receptor, strongly implicating NDF in the physiological transition. (iii) In sensory ganglia, the microenvironment is capable of negatively regulating Krox-20, presumably by preventing the conversion of satellite glial cells toward a Schwann cell-like phenotype.

Aguayo
A. J.
,
Epps
J.
,
Charron
L.
,
Bray
G. M.
(
1976
)
Multipotentiality of Schwann cells in cross-anastomosed and grafted myelinated and unmyelinated nerves: quantitative microscopy and radioautography.
Brain Research
104
,
1
20
Anderson
D. J.
(
1993
)
Cell and molecular biology of neural crest cell lineage diversification.
Curr. Opinion Neurobiol
3
,
8
13
Bolin
L. M.
,
Shooter
E. M.
(
1993
)
Neurons regulate Schwann cell genes by diffusible molecules.
J. Cell Biol
123
,
237
243
Brockes
J. P.
,
Fields
K. L.
,
Raff
M. C.
(
1979
)
Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve.
Brain Research
165
,
105
118
Brockes
J. P.
,
Raff
M. C.
,
Nishiguchi
D. J.
,
Winter
J.
(
1980
)
Studies on cultured rat Schwann cells. III. Assays for peripheral myelin proteins.
J. Neurocytology
9
,
67
77
Brunden
K. R.
,
Windebank
A. J.
,
Poduslo
J. F.
(
1990
)
Role of axons in the regulation of P0 biosynthesis by Schwann cells.
J. Neuroscience
26
,
135
143
Cameron-Curry
P.
,
Dulac
C.
,
Le Douarin
N. M.
(
1993
)
Negative regulation of Schwann cell myelin protein gene expression by the dorsal root ganglionic microenvironment.
Eur. J. Neurosci
5
,
594
604
Chavrier
P.
,
Zerial
M.
,
Lemaire
P.
,
Almendral
J.
,
Bravo
R.
,
Charnay
P.
(
1988
)
A gene encoding a protein with zinc fingers is activated during G0/G1 transition in cultured cells.
EMBO J
7
,
29
35
Chavrier
P.
,
Vesque
C.
,
Galliot
B.
,
Vigneron
M.
,
Dolle
P.
,
Duboule
D.
,
Charnay
P.
(
1990
)
The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1. 4 gene.
EMBO J
9
,
1209
1218
D'Amico-Martel
A.
,
Noden
D. M.
(
1983
)
Contributions of placodal and neural crest cells to avian cranial peripheral ganglia.
Amer. J. Anat
166
,
445
468
Dong
Z.
,
Brennan
A.
,
Liu
N.
,
Yarden
Y.
,
Lefkowitz
G.
,
Mirsky
R.
,
Jessen
K. R.
(
1995
)
Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors.
Neuron
15
,
585
596
Dulac
C.
,
Cameron-Curry
P.
,
Ziller
C.
,
Le Douarin
N. M.
(
1988
)
A surface protein expressed by avian myelinating and nonmyelinating Schwann cells but not by satellite or enteric glial cells.
Neuron
1
,
211
20
Eldridge
C. F.
,
Bunge
M. B.
,
Bunge
R. P.
,
Wood
P. M.
(
1987
)
Differentiation of axon-related Schwann cells in vitro. I. Ascorbic acid regulates basal lamina assembly and myelin formation.
J. Cell Biol
105
,
1023
34
Eldridge
C. F.
,
Bunge
B. M.
,
Bunge
R. P.
(
1989
)
Differentiation of axon related Schwann cells: II. Control of myelin formation by basal lamina.
J. Neurosci
9
,
625
638
Falls
D. L.
,
Rosen
K. M.
,
Corfas
G.
,
Lane
W. S.
,
Fischbach
G. D.
(
1993
)
ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the Neu ligand family.
Cell
72
,
801
815
Frank
E.
,
Sanes
J. R.
(
1991
)
Lineage of neurons and glia in chick dorsal root ganglia: analysis in vivo with a recombinant retrovirus.
Development
111
,
895
908
Fraser
S. E.
,
Bronner-Fraser
M.
(
1991
)
Migrating neural crest cells in the trunk of the avian embryo are multipotent.
Development
112
,
913
920
Gavrilovic
J.
,
Brennan
A.
,
Mirsky
R.
,
Jessen
K. R.
(
1995
)
Fibroblast growth factors and insulin growth factors combine to promote survival of rat Schwann cell precursors without induction of DNA synthesis.
European J. Neurosci
7
,
77
85
Holmes
W. E.
,
Sliwkowski
M. X.
,
Akita
R. W.
,
Henzel
W. J.
,
Lee
J.
,
Park
J. W.
,
Yansura
D.
,
Abadi
N.
,
Raab
H.
,
Lewis
G. D.
, et al. 
(
1992
)
Identification of heregulin, a specific activator of p185erB2.
Science
256
,
1205
1210
Jessen
K. R.
,
Morgan
L.
,
Stewart
H. J. S.
,
Mirsky
R.
(
1990
)
Three markers of adult non-myelin-forming Schwann cells, 217c(Ran-1), A5E3 and GFAP: development and regulation by neuron-Schwann cell interactions.
Development
109
,
91
103
Jessen
K. R.
,
Mirsky
R.
(
1991
)
Schwann cell precursors and their development.
Glia
4
,
185
194
Jessen
K. R.
,
Brennan
A.
,
Morgan
L.
,
Mirsky
R.
,
Kent
A.
,
Hashimoto
Y.
,
Gavrilovic
J.
(
1994
)
The Schwann cell precursor and its fate: a study of cell death and differentiation during gliogenesis in rat embryonic nerves.
Neuron
12
,
509
527
Le Douarin
N.
(
1986
)
Cell line segregation during peripheral nervous system ontogeny.
Science
231
,
1515
1522
Le Douarin
N.
,
Dulac
C.
,
Dupin
E.
,
Cameron-Curry
P.
(
1991
)
Glial cell lineages in the neural crest.
Glia
4
,
175
184
Lemke
G.
,
Chao
M.
(
1988
)
Axons regulate Schwann cell expression of the major myelin and NGF receptor genes.
Development
102
,
499
–.
Marchionni
M. A.
,
Goodearl
A. D. J.
,
Chen
M. S.
,
Bermingham-McDonogh
O.
,
Kirk
C.
,
Hendricks
M.
,
Danehy
F.
,
Misumi
D.
,
Sudhalter
J.
,
Kobayashi
K.
, et al. 
(
1993
)
Glial growth factors are alternatively spliced erB2 ligands expressed in the nervous system.
Nature
362
,
312
318
Meyer
D.
,
Birchmeier
C.
(
1994
)
Distinct isoforms of neuregulin are expressed in mesenchymal and neuronal cells during mouse development.
Proc. Natl. Acad. Sci. USA
91
,
1064
1068
Meyer
D.
,
Birchmeier
C.
(
1995
)
Multiple essential functions of neuregulin in development.
Nature
378
,
386
390
Mirsky
R.
,
Winter
J.
,
Abney
E. R.
,
Pruss
R. M.
,
Gavrilovic
J.
,
Raff
M. C.
(
1980
)
Myelin-specific proteins and glycolipids in rat Schwann cells and oligodendrocytes in culture.
J. Cell Biol
84
,
483
94
Monuki
E. S.
,
Kuhn
R.
,
Weinmaster
G.
,
Trapp
B. D.
,
Lemke
G.
(
1990
)
Expression and activity of the POU transcription factor SCIP.
Science
249
,
1300
1303
Morgan
L.
,
Jessen
K. R.
,
Mirsky
R.
(
1991
)
The effects of cAMP on differentiation of cultured Schwann cells: Progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP-, NGF-receptor-) growth inhibition.
J. Cell Biol
112
,
457
467
Morrison
S.
,
Mitchell
L. S.
,
Ecob-Prince
M. S.
,
Griffiths
I. R.
,
Thomson
C. E.
,
Barrie
J. A.
,
Kirkham
D.
(
1991
)
P0 gene expression in cultured Schwann cells.
J. Neurocytol
20
,
769
780
Neuberger
T. J.
,
Cornbrooks
C. J.
(
1989
)
Transient modulation of Schwann cell antigens after peripheral nerve transection and subsequent regeneration.
J. Neurocytol
18
,
695
710
Orr-Urtreger
A.
,
Trakhenbrot
L.
,
Ben-Levy
R.
,
Wen
D.
,
Rechavi
G.
,
Lonai
P.
,
Yarden
Y.
(
1993
)
Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-21.
Proc. Natl. Acad. Sci. USA
90
,
1867
1871
Owens
G. C.
,
Bunge
R. P.
(
1989
)
Evidence for an early role for myelin-associated glycoprotein in the process of myelination.
Glia
2
,
119
128
Placzek
M.
,
Jessell
T. M.
,
Dodd
J.
(
1993
)
Induction of floor plate differentiation by contact-dependent, homeogeneic signals.
Development
117
,
205
218
Raff
M. C.
,
Abney
E.
,
Brockes
J. P.
,
Hornby-Smith
A.
(
1978
)
Schwann cell growth factors.
Cell
15
,
813
822
Schneider-Maunoury
S.
,
Topilko
P.
,
Seitanidou
T.
,
Levi
G.
,
Cohen-Tannoudji
M.
,
Pournin
S.
,
Babinet
C.
,
Charnay
P.
(
1993
)
Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain.
Cell
75
,
1199
1214
Topilko
P.
,
Schneider-Maunoury
S.
,
Levi
G.
,
Baron-Van Evercooren
A.
,
Chennoufi
A. B. Y.
,
Seitanidou
T.
,
Babinet
C.
,
Charnay
P.
(
1994
)
Krox-20 controls myelination in the peripheral nervous system.
Nature
371
,
796
799
Vesque
C.
,
Charnay
P.
(
1992
)
Mapping functional regions of the segment-specific transcription factor Krox-20.
Nucleic Acids Res
20
,
2485
2492
Weinmaster
G.
,
Lemke
G.
(
1990
)
Cell-specific cyclic AMP-mediated induction of the PDGF receptor.
EMBO J
9
,
915
920
Wen
D.
,
Peles
E.
,
Cupples
R.
,
Suggs
S. V.
,
Bacus
S. S.
,
Luo
Y.
,
Trail
G.
,
Hu
S.
,
Silbiger
S. M.
,
Ben-Levy
R.
, et al. 
(
1992
)
Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit.
Cell
69
,
559
572
Wen
J. Y. M.
,
Morshead
C. M.
,
van der Kooy
D.
(
1994
)
Satellite cell proliferation in the adult rat trigeminal ganglion results from the release of a mitotic protein from explanted sensory neurons.
J. Cell Biol
124
,
1005
1015
Wilkinson
D.
,
Bhatt
S.
,
Chavrier
P.
,
Bravo
R.
,
Charnay
P.
(
1989
)
Segment-specific expression of a zinc finger gene in the developing nervous system of the mouse.
Nature
337
,
461
464
Wood
P. M.
(
1976
)
Separation of functional Schwann cells and neurons from normal peripheral nerve tissue.
Brain Research
115
,
361
375
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