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Vol. 14, No. 17, pp. 2134-2139, September 1, 2000
1 Hormone Research Institute, Department of Medicine, University of California-San Francisco, San Franscisco, California 94143 USA; 2 Center for Molecular Neurobiology, Hamburg, Germany; 3 Nina Ireland Laboratory of Developmental Neurobiology, University of California-San Francisco, San Francisco, California 94143 USA; 4 Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032 USA; 5 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S 17177 Stockholm, Sweden
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ABSTRACT |
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 Top
 Abstract
 Introduction
Results and Discussion
Materials and methods
References
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There is growing evidence that sonic hedgehog (Shh) signaling regulates ventral neuronal fate in the vertebrate central nervous system through Nkx-class homeodomain proteins. We have examined the patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1. These mutants show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons. At many axial levels there is a complete block in the generation of V2 interneurons and motor neurons and a compensatory ventral expansion in the domain of generation of V1 neurons, demonstrating the essential functions of Nkx6.1 in regional patterning and neuronal fate determination.
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Introduction |
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Top
Abstract
Introduction
Results and Discussion
Materials and methods
References
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During the development of the embryonic central nervous system
(CNS) the mechanisms that specify regional identity and neuronal fate are intimately linked (Anderson et al. 1997
; Lumsden and Krumlauf
1996; Rubenstein et al. 1998). In the ventral half of the CNS, for
example, the secreted factor Sonic hedgehog (Shh) has a fundamental
role in controlling both regional pattern and neuronal fate (Tanabe
and Jessell 1996; Ericson et al. 1997a; Hammerschmidt et al. 1997). Shh
appears to function as a gradient signal. In the spinal cord, five
distinct classes of neurons can be generated in vitro in response to
two- to threefold changes in the concentration of Shh, and the
position at which each neuronal class is generated in vivo is predicted
by the concentration required for their induction in vivo (Ericson et
al. 1997a,b; Briscoe et al. 2000). Thus, neurons generated in more
ventral regions of the neural tube require progressively higher
concentrations of Shh for their induction.
The genetic programs activated in neural progenitor cells in response
to Shh signaling, however, remain incompletely defined. Emerging
evidence suggests that homeobox genes function as critical intermediaries in the neural response to Shh signals (Lumsden and
Krumlauf 1996; Tanabe and Jessell 1996; Ericson et al. 1997a,b; Hammerschmidt et al. 1997; Rubenstein et al. 1998). Several homeobox genes are expressed by ventral progenitor cells, and their expression is regulated by Shh. Gain-of-function studies on homeobox gene action
in the chick neural tube have provided evidence that homeodomain proteins are critical for the interpretation of graded Shh signaling and that they function to delineate progenitor domains and control neuronal subtype identity (Briscoe et al. 2000). Consistent with these findings, the pattern of generation of neuronal subtypes in the basal telencephalon and in the ventral-most region of the spinal cord is perturbed in mice carrying mutations in certain Shh-regulated homeobox genes (Ericson et al. 1997b; Sussel et al. 1999;
Pierani et al., unpubl.).
Members of the Nkx class of homeobox genes are expressed by
progenitor cells along the entire rostro-caudal axis of the ventral neural tube, and their expression is dependent on Shh signaling (Rubenstein and Beachy 1998). Mutation in the Nkx2.1 or
Nkx2.2 genes leads to defects in ventral neural patterning
(Briscoe et al. 1999; Sussel et al. 1999), raising the possibility that
Nkx genes play a key role in the control of ventral patterning
in the ventral region of the CNS. Genetic studies to assess the role of
Nkx genes have, however, focused on only the most ventral
region of the neural tube. A recently identified Nkx gene,
Nkx6.1, is expressed more widely by most progenitor cells
within the ventral neural tube (Pabst et al. 1998; Qiu et al. 1998;
Briscoe et al. 1999), suggesting that it may have a prominent role in
ventral neural patterning. Here we show that in mouse embryos
Nkx6.1 is expressed by ventral progenitors that give rise to
motor (MN), V2, and V3 neurons. Mice carrying a null mutation of
Nkx6.1 exhibit a ventral-to-dorsal switch in the identity of
progenitor cells and a corresponding switch in the identity of the
neuronal subtype that emerges from the ventral neural tube. The
generation of MN and V2 neurons is markedly reduced, and there is a
ventral expansion in the generation of a more dorsal V1 neuronal
subtype. Together, these findings indicate that Nkx6.1 has a
critical role in the specification of MN and V2 neuron subtype identity
and, more generally, that Nkx genes play a role in the
interpretation of graded Shh signaling.
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Results and Discussion |
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Top
Abstract
Introduction
Results and Discussion
Materials and methods
References
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To define the role of Nkx6.1 in neural development, we
compared patterns of neurogenesis in the embryonic spinal cord and hindbrain of wild-type mice and mice lacking Nkx6.1 (Sander et al. 1998). In wild-type embryos, neural expression of Nkx6.1
is first detected at spinal cord and caudal hindbrain levels at about embryonic day 8.5 (E8.5; Qiu et al. 1998; data not shown), and by E9.5
the gene is expressed throughout the ventral third of the neural tube
(Fig. 1A). The expression of Nkx6.1 persists
until at least E12.5 (Fig. 1B,C; data not shown). Nkx6.1
expression was also detected in mesodermal cells flanking the ventral
spinal cord (Fig. 1B,C). To define more precisely the domain of
expression of Nkx6.1, we compared its expression with that of
10 homeobox genes
Pax3, Pax7, Gsh1, Gsh2, Irx3, Pax6, Dbx1,
Dbx1, Dbx2, and Nkx2.9that have been shown
to define discrete progenitor cell domains along the dorsoventral axis
of the ventral neural tube (Goulding et al. 1991; Valerius et al. 1995;
Ericson et al. 1997a,b; Pierani et al. 1999; Briscoe et al. 2000).
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This analysis revealed that the dorsal boundary of Nkx6.1 expression is positioned ventral to the boundaries of four genes expressed in by dorsal progenitor cells: Pax3, Pax7, Gsh1, and Gsh2 (Fig. 1I,N; data not shown). Within the ventral neural tube, the dorsal boundary of Nkx6.1 expression is positioned ventral to the domain of Dbx1 expression and close to the ventral boundary of Dbx2 expression (Fig. 1G,H,P). The domain of Pax6 expression extends ventrally into the domain of Nkx6.1 expression (Fig. 1O), whereas the expression of Nkx2.2 and Nkx2.9 overlaps with the ventral-most domain of Nkx6.1 expression (Fig. 1O,Q).
To address the function of Nkx6.1 in neural development, we
analyzed progenitor cell identity and the pattern of neuronal differentiation in Nkx6.1 null mutant mice (Sander et al.
1998). We detected a striking change in the profile of expression of three homeobox genes, Dbx2, Gsh1, and Gsh2,
in Nkx6.1 mutants. The domains of expression of Dbx2,
Gsh1, and Gsh2 each expanded into the ventral neural
tube (Fig. 1K-M; data not shown). At E10.5, Dbx2 was
expressed at high levels by progenitor cells adjacent to the floor
plate, but at this stage ectopic Dbx2 expression was detected
only at low levels in regions of the neural tube that generate motor
neurons (Fig. 1K). By E12.5, however, the ectopic ventral expression of
Dbx2 had become more uniform and now clearly included the
region of motor neuron and V2 neuron generation (Fig. 1L). Similarly,
in Nkx6.1 mutants, both Gsh1 and Gsh2 were
ectopically expressed in a ventral domain of the neural tube and also
in adjacent paraxial mesodermal cells (Fig. 1M; data not shown).
The ventral limit of Pax6 expression was unaltered in
Nkx6.1 mutants, although the most ventrally located cells
within this progenitor domain expressed a higher level of Pax6 protein
than those in wild-type embryos (Fig. 1O,S). We detected no change in the
patterns of expression of Pax3, Pax7, Dbx1, Irx3, Nkx2.2, or
Nkx2.9 in Nkx6.1 mutant embryos (Fig. 1R-U; data not
shown). Importantly, the level of Shh expression by floor plate cells was
unaltered in Nkx6.1 mutants (Fig. 1N,R). Thus, the loss of Nkx6.1 function deregulates the patterns of expression of a
selected subset of homeobox genes in ventral progenitor cells without
an obvious effect on Shh levels (Fig. 1D,E). The role of Shh in
excluding Dbx2 from the most ventral region of the neural tube
(Pierani et al. 1999) appears therefore to be mediated through the
induction of Nkx6.1 expression. Consistent with this view,
ectopic expression of Nkx6.1 represses Dbx2
expression in chick neural tube (Briscoe et al. 2000). The detection of
sites of ectopic Gsh1/2 expression in the paraxial mesoderm as
well as the ventral neural tube, both sites of Nkx6.1
expression, suggests that Nkx6.1 has a general role in
restricting Gsh1/2 expression. The signals that promote ventral Gsh1/2 expression in Nkx6.1 mutants remain
unclear but could involve factors other than Shh that are secreted by
the notochord (Hebrok et al. 1998).
The domain of expression of Nkx6.1 within the ventral neural
tube of wild-type embryos encompasses the progenitors of three main
neuronal classes: V2, MN, and V3 interneurons (Goulding et al. 1991;
Ericson et al. 1997a,b; Qiu et al. 1998; Briscoe et al. 1999, 2000;
Pierani et al. 1999; Fig. 2A-D). We examined whether the generation of any of these neuronal classes is impaired in Nkx6.1 mutants, focusing first on the generation of motor
neurons. In Nkx6.1 mutant embryos there was a marked reduction
in the number of spinal motor neurons, as assessed by expression of the
homeodomain proteins Lhx3, Isl1/2, and HB9 (Arber et al. 1999; Tsuchida
et al. 1994; Fig. 2E-L) and by expression of the gene encoding the transmitter synthetic enzyme choline acetyltransferase (data not shown). In addition, few if any axons were observed to emerge from the
ventral spinal cord (data not shown). The incidence of motor neuron
loss, however, varied along the rostrocaudal axis of the spinal
cord. Few if any motor neurons were detected at caudal cervical
and upper thoracic levels of Nkx6.1 mutants analyzed at
E11-E12.5 (Fig. 2M,N,Q,R), whereas motor neuron number was reduced
only by 50%-75% at more caudal levels (Fig. 2O,P,S,T; data not
shown). At all axial levels, the initial reduction in motor neuron
number persisted at both E12.5 and p0 (Fig. 2M-T; data not shown),
indicating that the loss of Nkx6.1 activity does not simply
delay motor neuron generation. Moreover, we detected no increase in the
incidence of TUNEL+ cells in Nkx6.1 mutants (data
not shown), providing evidence that the depletion of motor neurons does
not result solely from apoptotic death.
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The persistence of some spinal motor neurons in Nkx6.1 mutants
raised the possibility that the generation of particular subclasses of
motor neurons is selectively impaired. To address this issue, we
monitored the expression of markers of distinct subtypes of motor
neurons at both spinal and hindbrain levels of Nkx6.1 mutant embryos. At spinal levels, the extent of the reduction in the generation of motor neurons that populate the median (MMC) and lateral
(LMC) motor columns was similar in Nkx6.1 mutants as assessed by the number of motor neurons that coexpressed Isl1/2 and Lhx3 (defining MMC neurons; Fig. 3A,B) and by the
expression of Raldh2 (defining LMC neurons; Sockanathan and
Jessell 1998; Arber et al. 1999; Fig. 3C,D). In addition, the
generation of autonomic visceral motor neurons was reduced to an extent
similar to that of somatic motor neurons at thoracic levels of the
spinal cord of E12.5 embryos (data not shown). Thus, the loss of
Nkx6.1 activity depletes the major subclasses of spinal motor
neurons to a similar extent.
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At hindbrain levels, Nkx6.1 is expressed by the progenitors of
both somatic and visceral motor neurons (Fig. 3E,F; data not shown). We
therefore examined whether the loss of Nkx6.1 might selectively affect subsets of cranial motor neurons. We detected a
virtually complete loss in the generation of hypoglossal and abducens
somatic motor neurons in Nkx6.1 mutants, as assessed by the
absence of dorsally generated HB9+ motor neurons (Fig. 3G,H;
data not shown; Arber et al. 1999; Briscoe et al. 1999). In contrast,
there was no change in the initial generation of any of the cranial
visceral motor neuron populations, assessed by coexpression of
Isl1 and Phox2a (Briscoe et al. 1999; Pattyn et al.
1997) within ventrally generated motor neurons (Fig. 3I,J; data not
shown). Moreover, at rostral cervical levels, the generation of spinal
accessory motor neurons (Ericson et al. 1997a,b) was also preserved in
Nkx6.1 mutants (data not shown). Thus, in the hindbrain the
loss of Nkx6.1 activity selectively eliminates the generation
of somatic motor neurons, while leaving visceral motor neurons intact.
Cranial visceral motor neurons, unlike spinal visceral motor neurons,
derive from progenitors that express the related Nkx genes
Nkx2.2 and Nkx2.9 (Briscoe et al. 1999). The
preservation of cranial visceral motor neurons in Nkx6.1
mutant embryos may therefore reflect the dominant activities of
Nkx2.2 and Nkx2.9 within these progenitor cells.
We next examined whether the generation of ventral interneurons is
affected by the loss of Nkx6.1 activity. V2 and V3
interneurons are defined, respectively, by expression of Chx10
and Sim1 (Arber et al. 1999; Briscoe et al. 1999; Fig.
4A,G). A severe loss of Chx10 V2 neurons was
detected in Nkx6.1 mutants at spinal cord levels (Fig. 4B),
although at hindbrain levels of Nkx6.1, mutants ~50% of V2
neurons persisted (data not shown). In contrast, there was no change in
the generation of Sim1 V3 interneurons at any axial level of
Nkx6.1 mutants (Fig. 4H). Thus, the elimination of
Nkx6.1 activity affects the generation of only one of the two major classes of ventral interneurons that derive from the
Nkx6.1 progenitor cell domain.
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Evx1+, Pax2+ V1 interneurons derive from progenitor
cells located dorsal to the Nkx6.1 progenitor domain (Fig. 4B)
within a domain that expresses Dbx2 but not Dbx1
(Burrill et al. 1997; Matise and Joyner 1997; Pierani et al. 1999).
Because Dbx2 expression undergoes a marked ventral expansion
in Nkx6.1 mutants, we examined whether there might be a
corresponding expansion in the domain of generation of V1 neurons. In
Nkx6.1 mutants, the region that normally gives rise to V2
neurons and motor neurons now also generated V1 neurons, as assessed by
the ventral shift in expression of the En1 and Pax2 homeodomain
proteins (Fig. 4B,C,E,F). Consistent with this, there was a two- to
threefold increase in the total number of V1 neurons generated in
Nkx6.1 mutants (Fig. 4C,D). In contrast, the domain of
generation of Evx1/2 V0 neurons, which derive from the Dbx1
progenitor domain (Pierani et al. 1999), was unchanged in
Nkx6.1 mutants (Fig. 4I,J). Thus, the ventral expansion in
Dbx2 expression is accompanied by a selective switch in
interneuronal fates from V2 neurons to V1 neurons. In addition, we
observed that some neurons within the ventral spinal cord of Nkx6.1 mutants coexpressed the V1 marker En1 and the
V2 marker Lhx3 (Fig. 4K,L). The coexpression of these markers
is rarely if ever observed in single neurons in wild-type embryos
(Ericson et al. 1996). Thus, within individual neurons in
Nkx6.1 mutants, the ectopic program of V1 neurogenesis appears
to be initiated in parallel with a residual, albeit transient, program
of V2 neuron generation. This result complements observations in
Hb9 mutant mice, in which the programs of V2 neuron and motor
neuron generation coincide transiently within individual neurons (Arber
et al. 1999; Thaler et al. 1999).
Taken together, our findings reveal an essential role for the
Nkx6.1 homeobox gene in the specification of regional pattern and neuronal fate in the ventral half of the mammalian CNS. Within the
broad ventral domain within which Nkx6.1 is expressed (Fig. 5A), its activity is required to promote MN and V2
interneuron generation and to restrict the generation of V1
interneurons (Fig. 5B). We favor the idea that the loss of MN and V2
neurons is a direct consequence of the loss of Nkx6.1
activity, as the depletion of these two neuronal subtypes is evident at
stages when only low levels of Dbx2 are expressed ectopically
in most regions of the ventral neural tube. Nonetheless, we can not
exclude that low levels of ectopic ventral Dbx2 expression
could contribute to the block in motor neuron generation. Consistent
with this view, the ectopic expression of Nkx6.1 is able to
induce both motor neurons and V2 neurons in chick neural tube (Briscoe
et al. 2000). V3 interneurons and cranial visceral motor neurons derive
from a set of Nkx6.1 progenitors that also express
Nkx2.2 and Nkx2.9 (Briscoe et al. 1999; Fig. 5A). The
generation of these two neuronal subtypes is unaffected by the loss of
Nkx6.1 activity, suggesting that the actions of
Nkx2.2 and Nkx2.9 dominate over that of
Nkx6.1 within these progenitors. The persistence of some spinal motor neurons and V2 neurons in Nkx6.1 mutants could
reflect the existence of a functional homologue within the caudal
neural tube.
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The role of Nkx6.1 revealed in these studies, taken together
with previous findings, suggests a model in which the spatially restricted expression of Nkx genes within the ventral neural
tube (Fig. 5) has a pivotal role in defining the identity of ventral cell types induced in response to graded Shh signaling. Strikingly, in
Drosophila, the Nkx gene NK2 has been shown
to have an equivalent role in specifying neuronal fates fate in the
ventral nerve cord (Chu et al. 1998; McDonald et al. 1998). Moreover,
the ability of Nkx6.1 to function as a repressor of the
dorsally expressed Gsh1/2 homeobox genes parallels the ability
of Drosophila NK2 to repress Ind, a
Gsh1/2-like homeobox gene (Weiss et al. 1998). Thus, the
evolutionary origin of regional pattern along the dorsoventral axis of
the central nervous system may predate the divergence of invertebrate
and vertebrate organisms.
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Materials and methods |
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Top
Abstract
Introduction
Results and Discussion
Materials and methods
References
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Generation of Nkx6.1 null mutation
A null mutation in Nkx6.1 was generated by gene targeting in 129-strain ES cells by excising an 800-bp NotI fragment containing part of exon1 and replacing it by a PGK-neo cassette (M. Sander and M. German, unpubl.). Mutants were born at Mendelian frequency and died soon after birth; they exhibited movements only upon tactile stimulation.
Immunocytochemistry and in situ hybridization
Localization of mRNA was performed by in situ hybridization
following the method of Schaeren-Wiemers and Gerfin-Moser (1993). The
Dbx2 riboprobe comprised the 5' EcoR1 fragment of
the mouse cDNA (Pierani et al. 1999). Probes for other cDNAs were cited in the text and used as described therein. Protein expression was
localized by indirect fluorescence immunocytochemistry or peroxidase
immunohistochemistry (Briscoe et al. 1999; Ericson et al. 1997b).
Nkx6.1 was detected with a rabbit antiserum (Briscoe et al.
1999). Antisera against Shh, Pax7, Isl1/2, HB9, Lhx3, Chx10, Phox2a/b,
En1, and Pax2 have been described (Briscoe et al. 1999; Ericson et al.
1997b). Fluorescence detection was carried out using an MRC 1024 Confocal Microscope (BioRad).
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Acknowledgments |
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We thank K. MacArthur and S. Yu for help in preparing the manuscript; the following people for cDNAs: P. Gruss, S. Potter, F.Ruddle, R. McInnes, A. Joyner, G. Martin, M.Tessier-Lavigne, and C. Gall; J.F. Brunet for Phox2; and H. Westphal for Lhx3 antibodies. JLRR is supported by Nina Ireland, NARSAD, NIDA (R01DA12462), and NIMH K02 MH01046-01, J.B. is a research associate of the Howard Hughes Medical Institute, J.E. is supported by the Swedish Foundation for Strategic research, the Swedish National Science Research Council, the Karolinska Institute, and the Harald and Greta Jeanssons Foundation. M.G. is supported by NIH (grants DK41822 and DK21344). M.S. was supported by the Deutsche Forschungsgemeinschaft and the Juvenile Diabetes Foundation International. T.J. is supported by NIH and is an Investigator of the Howard Hughes Research Institute.
The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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Footnotes |
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[Key Words: Nkx; spinal cord; motor neurons; neuronal specification; interneurons]
Received May 18, 2000; revised version accepted July 11, 2000.
6 These authors contributed equally to this work.
7 Corresponding author.
E-MAIL jlrr{at}cgl.ucsf.edu; FAX (415) 502-7618.
Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.820400.
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References |
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Abstract
Introduction
Results and Discussion
Materials and methods
References
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A. Pattyn, A. Vallstedt, J. M. Dias, M. Sander, and J. Ericson Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain Development, September 1, 2003; 130(17): 4149 - 4159. [Abstract] [Full Text] [PDF]
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Y. Jeong and D. J. Epstein Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node Development, August 15, 2003; 130(16): 3891 - 3902. [Abstract] [Full Text] [PDF]
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