Motor neurons are a widely studied model of vertebrate neurogenesis. They can be subdivided in somatic, branchial and visceral motor neurons. Recent studies on the dorsoventral patterning of the rhombencephalon have implicated the homeobox genes Pax6 and Nkx2.2 in the early divergence of the transcriptional programme of hindbrain somatic and visceral motor neuronal differentiation. We provide genetic evidence that the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain. In mice lacking Phox2b, both the generic and subtype-specific programs of motoneuronal differentiation are disrupted at an early stage. Most motor neuron precursors die inside the neuroepithelium while those that emigrate to the mantle layer fail to switch on early postmitotic markers and to downregulate neuroepithelial markers. Thus, the loss of function of Phox2b in hindbrain motor neurons exemplifies a novel control point in the generation of CNS neurons.

REFERENCES

Arber
S.
,
Han
B.
,
Mendelsohn
M.
,
Smith
M.
,
Jessell
T.M.
,
Sockanathan
S.
(
1999
)
Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity.
Neuron
23
,
659
674
Briscoe
J.
,
Sussel
L.
,
Serup
P.
,
Hartigan-O'Connor
D.
,
Jessell
T. M.
,
Rubenstein
J. L.
,
Ericson
J.
(
1999
).
Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling.
Nature
398
,
622
627
Brunet
J.-F.
,
Ghysen
A.
(
1999
)
Deconstructing cell determination: proneural genes and neuronal identity.
BioEssays
21
,
313
318
Edlund
T.
,
Jessell
T. M.
(
1999
)
Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system.
Cell
96
,
211
224
Ericson
J.
,
Rashbass
P.
,
Schedl
A.
,
Brenner-Morton
S.
,
Kawakami
A.
,
van Heyningen
V.
,
Jessell
T. M.
,
Briscoe
J.
(
1997
)
Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.
Cell
90
,
169
180
Escurat
M.
,
Djabali
K.
,
Gumpel
M.
,
Gros
F.
,
Portier
M. M.
(
1990
)
Differential expression of two neuronal intermediate-filament proteins, peripherin and the low-molecular-mass neurofilament protein (NF-L), during the development of the rat.
J. Neurosci
10
,
764
784
Fode
C.
,
Gradwohl
G.
,
Morin
X.
,
Dierich
A.
,
LeMeur
M.
,
Goridis
C.
,
Guillemot
F.
(
1998
)
The bHLH protein NEUROGENIN 2 is a determination factor for epibranchial placode-derived sensory neurons.
Neuron
20
,
483
494
Fritzsch
B.
,
Northcutt
R. G.
(
1993
)
Cranial and spinal nerve organization in amphioxus and lampreys: evidence for an ancestral craniate pattern.
Acta Anat
148
,
96
109
Fritzsch
B.
,
Northcutt
R. G.
(
1993
)
Origin and migration of trochlear, oculomotor and abducent motor neurons in Petromyzon marinus L.
Dev. Brain Res
74
,
122
126
Garel
S.
,
Marin
F.
,
Mattei
M. G.
,
Vesque
C.
,
Vincent
A.
,
Charnay
P.
(
1997
)
Family of Ebf/Olf-1-related genes potentially involved in neuronal differentiation and regional specification in the central nervous system.
Dev. Dyn
210
,
191
205
Grove
E. A.
,
Tole
S.
,
Limon
J.
,
Yip
L.
,
Ragsdale
C. W.
(
1998
)
The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice.
Development
125
,
2315
2325
Guillemot
F.
,
Lo
L. C.
,
Johnson
J. E.
,
Auerbach
A.
,
Anderson
D. J.
,
Joyner
A. L.
(
1993
)
Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons.
Cell
75
,
463
476
Guo
S.
,
Brush
J.
,
Teraoka
H.
,
Goddard
A.
,
Wilson
S. W.
,
Mullins
M. C.
,
Rosenthal
A.
(
1999
)
Development of noradrenergic neurons in the Zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a.
Neuron
24
,
555
566
Guthrie
S.
,
Butcher
M.
,
Lumsden
A.
(
1991
)
Patterns of cell division and interkinetic nuclear migration in the chick embryo hindbrain.
J. Neurobiol
22
,
742
754
Hirsch
M. R.
,
Tiveron
M. C.
,
Guillemot
F.
,
Brunet
J.-F.
,
Goridis
C.
(
1998
)
Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system.
Development
125
,
599
608
Johnson
J. E.
,
Birren
S. J.
,
Anderson
D. J.
(
1990
)
Two rat homologues of Drosophila achaete-scute specifically expressed in neuronal precursors.
Nature
346
,
858
861
Karlsson
O.
,
Thor
S.
,
Norberg
T.
,
Ohlsson
H.
,
Edlund
T.
(
1990
)
Insulin gene enhancer binding protein Isl-1 is a member of a novel class of protein containing both a homeo-and a Cys-His domain.
Nature
344
,
879
882
Knittel
T.
,
Kessel
M.
,
Kim
M. H.
,
Gruss
P.
(
1995
)
A conserved enhancer of the human and murine Hoxa-7 gene specifies the anterior boundary of expression during embryonal development.
Development
121
,
1077
1088
Lo
L.
,
Tiveron
M. C.
,
Anderson
D. J.
(
1998
)
MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity.
Development
125
,
609
620
Lo
L.
,
Morin
X.
,
Brunet
J.-F.
,
Anderson
D. J.
(
1999
)
Specification of neurotransmitter identity by Phox2 proteins in neural crest stem cells.
Neuron
22
,
693
705
Lumsden
A.
,
Krumlauf
R.
(
1996
)
Patterning the vertebrate neuraxis.
Science
274
,
1109
1115
Ma
Q.
,
Sommer
L.
,
Cserjesi
P.
,
Anderson
D. J.
(
1997
)
Mash1 and neurogenin1 expression patterns define complementary domains of neuroepithelium in the developing CNS and are correlated with regions expressing Notch ligands.
J. Neurosci
17
,
3644
3652
Ma
Q.
,
Chen
Z.
,
del Barco Barrantes
I.
,
de la Pompa
J. L.
,
Anderson
D. J.
(
1998
)
neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia.
Neuron
20
,
469
482
McKay
I. J.
,
Lewis
J.
,
Lumsden
A.
(
1997
)
Organization and development of facial motor neurons in the kreisler mutant mouse.
Eur. J. Neurosci
9
,
1499
1506
Morin
X.
,
Cremer
H.
,
Hirsch
M.-R.
,
Kapur
R. P.
,
Goridis
C.
,
Brunet
J.-F.
(
1997
)
Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a.
Neuron
18
,
411
423
Osumi
N.
,
Hirota
A.
,
Ohuchi
H.
,
Nakafuku
M.
,
Iimura
T.
,
Kuratani
S.
,
Fujiwara
M.
,
Noji
S.
,
Eto
K.
(
1997
)
Pax-6 is involved in the specification of hindbrain motor neuron subtype.
Development
124
,
2961
2972
Pattyn
A.
,
Morin
X.
,
Cremer
H.
,
Goridis
C.
,
Brunet
J.-F.
(
1997
)
Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.
Development
124
,
4065
4075
Pattyn
A.
,
Morin
X.
,
Cremer
H.
,
Goridis
C.
,
Brunet
J.-F.
(
1999
)
The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.
Nature
399
,
366
370
Pfaff
S. L.
,
Mendelsohn
M.
,
Stewart
C. L.
,
Edlund
T.
,
Jessell
T. M.
(
1996
)
Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.
Cell
84
,
309
320
Roztocil
T.
,
Matter-Sadzinski
L.
,
Alliod
C.
,
Ballivet
M.
,
Matter
J. M.
(
1997
)
NeuroM, a neural helix-loop-helix transcription factor, defines a new transition stage in neurogenesis.
Development
124
,
3263
3272
Sharma
K.
,
Sheng
H. Z.
,
Lettieri
K.
,
Li
H.
,
Karavanov
A.
,
Potter
S.
,
Westphal
H.
,
Pfaff
S. L.
(
1998
)
LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons.
Cell
95
,
817
828
Shimamura
K.
,
Hartigan
D. J.
,
Martinez
S.
,
Puelles
L.
,
Rubenstein
J. L.
(
1995
)
Longitudinal organization of the anterior neural plate and neural tube.
Development
121
,
3923
3933
Stanke
M.
,
Junghans
D.
,
Geissen
M.
,
Goridis
C.
,
Ernsberger
U.
,
Rohrer
H.
(
1999
)
The Phox2 homeodomain proteins are sufficient to promote the development of sympathetic neurons.
Development
126
,
4087
4094
Taber Pierce
E.
(
1972
)
Time of origin of neurons in the brain stem of the mouse.
Progr. Brain Res
40
,
53
65
Takebayashi
K.
,
Takahashi
S.
,
Yokota
C.
,
Tsuda
H.
,
Nakanishi
S.
,
Asashima
M.
,
Kageyama
R.
(
1997
)
Conversion of ectoderm into a neural fate by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal.
EMBO J
16
,
384
395
Tanabe
Y.
,
William
C.
,
Jessell
T. M.
(
1998
)
Specification of motor neuron identity by the MNR2 homeodomain protein.
Cell
95
,
67
80
Thaler
J.
,
Harrison
K.
,
Sharma
K.
,
Lettieri
K.
,
Kehrl
J.
,
Pfaff
S. L.
(
1999
)
Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9.
Neuron
23
,
675
687
Thomas
S. A.
,
Palmiter
R. D.
(
1997
)
Disruption of the dopamine beta-hydroxylase gene in mice suggests roles for norepinephrine in motorfunction, learning, and memory.
Behavioral Neuroscience
111
,
579
589
Tiveron
M. C.
,
Hirsch
M.-R.
,
Brunet
J.-F.
(
1996
)
The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system.
J. Neurosci
16
,
7649
7660
Varela-Echavarria
A.
,
Pfaff
S. L.
,
Guthrie
S.
(
1996
)
Differential expression of LIM homeobox genes among motor neuron subpopulations in the developing chick brain stem.
Mol. Cell. Neurosci
8
,
242
257
Wang
S. S.
,
Tsai
R. Y. L.
,
Reed
R. R.
(
1997
)
The characterization of the Olf-1/EBF-like HLH transcription factor family: Implications in olfactory gene regulation and neuronal development.
J. Neurosci
17
,
4149
4158
This content is only available via PDF.