The diverse neuronal subtypes in the adult central nervous system arise from progenitor cells specified by the combined actions of anteroposterior (AP) and dorsoventral (DV) signaling molecules in the neural tube. Analyses of the expression and targeted disruption of the homeobox gene Hoxb1 demonstrate that it is essential for patterning progenitor cells along the entire DV axis of rhombomere 4 (r4). Hoxb1 accomplishes this function by acting very early during hindbrain neurogenesis to specify effectors of the sonic hedgehog and Mash1 signaling pathways. In the absence of Hoxb1 function, multiple neurons normally specified within r4 are instead programmed for early cell death. The findings reported here provide evidence for a genetic cascade in which an AP-specified transcription factor, Hoxb1, controls the commitment and specification of neurons derived from both alar and basal plates of r4.

REFERENCES

Altman
J.
,
Bayer
S. A.
(
1980
)
Development of the brain stem in the rat. 11. Thymidine-radiographic study of the time of origin of neurons of the upper medulla, excluding the vestibular and auditory nuclei.
J. Comp. Neurol
194
,
37
56
Barrow
J. R.
,
Capecchi
M. R.
(
1996
)
Targeted disruption of the hoxb-2 locus in mice interferes with expression of hoxb-1 and hoxb-4.
Development
122
,
3817
3828
Bell
E.
,
Wingate
R. J.
,
Lumsden
A.
(
1999
)
Homeotic transformation of rhombomere identity after localized Hoxb1 expression.
Science
284
,
2168
2171
Briscoe
J.
,
Pierani
A.
,
Jessell
T. M.
,
Ericson
J.
(
2000
)
A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube.
Cell
101
,
435
445
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
Carpenter
E. M.
,
Goddard
J. M.
,
Chisaka
O.
,
Manley
N. R.
,
Capecchi
M. R.
(
1993
).
Loss of Hox-A1 (Hox-1.6) function results in the reorganization of the murine hindbrain.
Development
118
,
1063
1075
Chiang
C.
,
Litingtung
Y.
,
Lee
E.
,
Young
K.E.
,
Corden
J.L.
,
Westphal
H.
,
Beachy
P.A.
(
1996
)
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Nature
383
,
407
413
Davenne
M.
,
Maconochie
M. K.
,
Neun
R.
,
Pattyn
A.
,
Chambon
P.
,
Krumlauf
R.
,
Rijli
F. M.
(
1999
)
Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain.
Neuron
22
,
677
691
Dolle
P.
,
Izpisúa-Belmonte
J.-C.
,
Falkenstein
H.
,
Renucci
A.
,
Duboule
D.
(
1989
)
Coordinate expression of the murine Hox-5 complex homeobox-containing genes during limb pattern formation.
Nature
342
,
767
772
Duboule
D.
(
1998
)
Vertebrate hox gene regulation: clustering and/or colinearity?.
Curr. Opin. Genet. Dev
8
,
514
518
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.
,
Morton
S.
,
Kawakami
A.
,
Roelink
H.
,
Jessell
T. M.
(
1996
)
Two critical periods of sonic hedgehog signaling required for specification of motor neuron identity.
Cell
87
,
661
673
Ericson
J.
,
Rashbass
P.
,
Schedl
A.
,
Brenner-Morton
S.
,
Kawakami
A.
,
van Heynigen
V.
,
Jessell
T. M.
(
1997
)
Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.
Cell
90
,
169
189
Flanagan
J. G.
,
Vanderhaeghen
P.
(
1998
)
The ephrins and Eph receptors in neural development.
Annu. Rev. Neurosci
21
,
309
345
Fode
C.
,
Gradwohl
G.
,
Morin
X.
,
Dierich
A.
,
LeMur
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
Frohman
M. A.
,
Boyle
M.
,
Martin
G. R.
(
1990
).
Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm.
Development
110
,
589
607
Goddard
J. M.
,
Rossel
M.
,
Manley
N. R.
,
Capecchi
M. R.
(
1996
)
Mice with targeted disruption of Hoxb1 fail to form the motor nucleus of the VIIth nerve.
Development
122
,
3217
3228
Godwin
A. R.
,
Stadler
H. S.
,
Nakamura
K.
,
Capecchi
M. R.
(
1998
)
Detection of targeted GFP-Hox gene fusions during mouse embryogenesis.
Proc. Natl. Acad. Sci. USA
95
,
13042
13047
Gradwohl
G.
,
Fode
C.
,
Guillemot
F.
(
1996
)
Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors.
Dev. Biol
180
,
227
241
Graham
A.
,
Papalopulu
N.
,
Krumlauf
R.
(
1989
)
The murine and Drosophila homeobox gene complexes have common features of organization and expression.
Cell
57
,
367
378
Guillemot
F.
,
Lo.
L.
,
Johnson
J. E.
,
Auerbach
A.
,
Anderson
D. J.
,
Joyner
A. L.
(
1993
)
Mammalian achaete-scute homolog 1is required for early development of olfactory and autonomic neurons.
Cell
75
,
463
476
Heitzler
P.
,
Bourouis
M.
,
Ruel
L.
,
Carteret
C.
,
Simpson
P.
(
1996
)
Genes of the Enhancer of split and achaete-scute complexes are required for a regulatory loop between Notch and Delta during lateral signalling in Drosophila.
Development
122
,
161
171
Hirsch
M.
,
Tiveron
M.
,
Buillemot
F.
,
Brunet
J.
,
Goridis
C.
(
1998
)
Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system.
Development
125
,
599
608
Jan
Y. N.
,
Jan
L. Y.
(
1994
)
Genetic control of cell fate specification in Drosophila peripheral nervous system.
Annu. Rev. Genet
28
,
373
393
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
Jungbluth
S.
,
Bell
E.
,
Lumsden
A.
(
1999
)
Specification of distinct motor neuron identities by the singular activities of individual Hox genes.
Development
126
,
2751
2758
Kageyama
R.
,
Nakanishi
S.
(
1997
)
Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system.
Curr. Opin. Genet. Dev
7
,
659
665
Krumlauf
R.
(
1994
)
Hox genes in vertebrate development.
Cell
78
,
191
201
Lee
J. E.
(
1997
)
Basic helix-loop-helix genes in neural development.
Curr. Opin. Neurobiol
7
,
13
20
Lumsden
A.
,
Keynes
R.
(
1989
)
Segmental patterns of neuronal development in the chick hindbrain.
Nature
337
,
424
428
Lumsden
A.
(
1990
)
The cellular basis of segmentation in the developing hindbrain.
Trends Neurosci
13
,
329
335
Lumsden
A.
,
Krumlauf
R.
(
1996
)
Patterning the vertebrate neuraxis.
Science
274
,
1109
1115
Ma
Q.
,
Kintner
C.
,
Anderson
D.J.
(
1996
)
Identification of neurogenin, a vertebrate neuronal determination gene.
Cell
87
,
43
52
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
Ma
Q.
,
Fode
C.
,
Guillemot
F.
,
Anderson
D. J.
(
1999
)
Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia.
Genes Dev
13
,
1717
1728
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
Manley
N. R.
,
Capecchi
M. R.
(
1995
)
The role of hoxa-3 in mouse thymus and thyroid development.
Development
121
,
1989
2003
Mansour
S. J.
,
Thomas
K. R.
,
Capecchi
M. R.
(
1988
)
Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes.
Nature
336
,
348
352
Marin
F.
,
Puelles
L.
(
1995
)
Morphological fate of rhombomeres in quail/chick chimeras: a segmental analysis of hindbrain nuclei.
Eur. J. Neurosci
7
,
1714
1738
Mark
M.
,
Lufkin
T.
,
Vonesch
J.-L.
,
Ruberte
E.
,
Olivo
J.-C.
,
Dolle
P.
,
Gorry
P.
,
Lumsden
A.
,
Chambon
P.
(
1993
)
Two rhombomeres are altered in Hoxa-1 mutant mice.
Development
119
,
319
338
McConnell
S. K.
(
1995
)
Constructing the cerebral cortex: neurogenesis and fate determination.
Neuron
15
,
761
768
Murphy
P.
,
Davidson
D. R.
,
Hill
R. E.
(
1989
)
Segment-specific expression of a homeobox-containing gene in the mouse hindbrain.
Nature
341
,
156
159
Murphy
P.
,
Hill
R. E.
(
1991
).
Expression of the mouse labial-like homeobox-containing genes, Hox 2.9 and Hox 1.6, during segmentation of the hindbrain.
Development
111
,
61
74
Nagy
A.
,
Rossant
J.
,
Abramow-Newerly
W.
,
Roder
J. C.
(
1993
)
Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
Proc. Natl. Acad. Sci. USA
90
,
8424
8428
Olson
E. N.
,
Arnold
H.-H.
,
Rigby
P. W. J.
,
Wold
B. J.
(
1996
)
Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4.
Cell
85
,
1
4
Panin
V. M.
,
Papayannopoulos
V.
,
Wilson
R.
,
Irvine
K. D.
(
1997
)
Fringe modulates Notch-ligand interactions.
Nature
387
,
908
912
Pata
I.
,
Studer
M.
,
van Doorninck
J. H.
,
Briscoe
J.
,
Kuuse
S.
,
Engel
J. D.
,
Grosveld
F.
,
Karis
A.
(
2000
)
The transcription factor GATA3 is a downstream effector of Hoxb1 specification in rhombomere 4.
Development
126
,
5523
5531
Pattyn
A.
,
Hirsch
M.
,
Goridis
C.
,
Brunet
J. F.
(
2000
)
Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b.
Development
127
,
1349
1358
Pattyn
A.
,
Morin
X.
,
Cremer
H.
,
Goridis
C.
,
Brunet
J.
(
1997
)
Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.
Development
124
,
4065
4075
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
Pierani
A.
,
Brenner-Morton
S.C.C.
,
Jessell
T. M.
(
1999
)
A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord.
Cell
97
,
903
915
Pöpperl
H.
,
Bienz
M.
,
Studer
M.
,
Chan
S.
,
Aparicio
S.
,
Brenner
S.
,
Mann
R. S.
,
Krumlauf
R.
(
1995
)
Segmented expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx.
Cell
81
,
1031
1042
Rossel
M.
,
Capecchi
M. R.
(
1999
)
Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development.
Development
126
,
5027
5040
Ruiz i Altaba
A.
,
Prezioso
V. R.
,
Darnell
J. E.
,
Jessell
T. M.
(
1993
)
Sequential expression of HNF-3 beta and HNF-3 alpha by embryonic organizing centers: the dorsal lip/node, notochord and floor plate.
Mech. Dev
44
,
91
108
Sasai
Y.
(
1998
)
Identifying the missing link: genes that connect neural induction and primary neurogenesis in vertebrate embryos.
Neuron
21
,
455
458
Schwenk
F.
,
Baron
U.
,
Rajewsky
K.
(
1995
)
A cre- transgenic mouse strain for the ubiquitous deletion of loxP- flanked gene segments including deletion in germ cells.
Nucleic Acids Res
23
,
5080
5081
Sockanathan
S.
,
Jessell
T. M.
(
1998
)
Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons.
Cell
94
,
503
514
Studer
M.
,
Lumsden
A.
,
Ariza-McNaughton
L.
,
Bradley
A.
,
Krumlauf
R.
(
1996
)
Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb1.
Nature
384
,
630
634
Taber Pierce
E.
(
1973
)
Time of origin of neurons in the brain stem of the mouse.
Prog. Brain Res
40
,
53
65
Tanabe
Y.
,
Jessell
T. M.
(
1996
)
Diversity and pattern in the developing spinal cord.
Science
274
,
1115
1123
Tsuchida
T.
,
Ensini
M.
,
Morton
S. B.
,
Baldassare
M.
,
Edlund
T.
,
Jessell
T. M.
,
Pfaff
S. L.
(
1995
)
Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes.
Cell
79
,
957
970
Wei
Y.
,
Yu
L.
,
Bowen
J.
,
Gorovsky
M. A.
,
Allis
C. D.
(
1999
)
Phosphorylation of histone H3 is required for proper chromosome condensation and segregation.
Cell
97
,
99
109
Weinstein
D. C.
,
Ruiz i Altaba
A.
,
Chen
W. S.P.H.
,
Prezioso
V. R.
,
Jessell
T. M.
,
Darnell
J. E. J.
(
1994
)
The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo.
Cell
78
,
575
588
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