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First published online May 11, 2006
doi: 10.1242/10.1242/dev.02345
1 Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Strasse
10, 13125 Berlin-Buch, Germany.
2 Department of Genetics and Howard Hughes Medical Institute, Harvard Medical
School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
3 National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7
1AA, UK.
* Author for correspondence (e-mail: cbirch{at}mdc-berlin.de)
Accepted 3 March 2006
 |
SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Asymmetric cell division, Neuronal specification, Spinal cord, Mash1 (Ascl1), Mouse, Chick
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Hunt and Mantyh, 2001;
Julius and Basbaum, 2001). The
developmental mechanisms that generate this neuronal diversity are
incompletely understood.
Neuroepithelial cells in the developing nervous system produce a remarkable
variety of neural cell types in a spatially and temporally controlled manner.
Many spinal cord neuronal subtypes are generated from distinct stripes of
progenitors that have been patterned by dorsal and ventral signals
(Caspary and Anderson, 2003;
Helms and Johnson, 2003;
Jessell, 2000;
Lee and Jessell, 1999). In the
dorsal spinal cord, six dorsal neuronal cell types (dI1-dI6) arise from
stripes of progenitors during the early developmental phase (E10-E11.5). As
development of the dorsal spinal cord proceeds, pronounced temporal and
spatial changes in specification of neural cells occur. At E12-E14.5, the
majority of the dorsal progenitor domain produces two neuronal subtypes, dILA
and dILB, which arise in a salt-and-pepper pattern
(Gross et al., 2002;
Müller et al., 2002).
dILA and dILB neurons are defined by the expression of the homeodomain factors
Pax2/Lhx1/5/Lbx1 and Tlx3/Lmx1b/Lbx1, respectively. Homeodomain factors that
first appear in postmitotic dILA and dILB neurons determine their further
differentiation program. Lbx1 acts as an upstream regulator, and dILA and dILB
neurons are not correctly specified in Lbx1 mutant mice
(Gross et al., 2002;
Müller et al., 2002).
Recently, the essential role of Tlx3 for the generation of excitatory
glutamatergic neurons in the dorsal spinal cord and of Lbx1 and
Pax2 in the specification of inhibitory GABAergic neurons has been
demonstrated (Cheng et al.,
2004; Cheng et al.,
2005). Lmx1b and Drg11 are essential for
terminal differentiation of neurons that settle in the uppermost layers of the
spinal cord, which process information from nociceptive sensory neurons
(Chen et al., 2001;
Ding et al., 2004). dILA and
dILB neurons arise from a progenitor domain that expresses Mash1
(Ascl1 – Mouse Genome Informatics) and Gsh1/2. The
role of Mash1 in the development of dILA and dILB neurons has not
been assessed.
Transcription factors of the basic helix-loop-helix family have important
roles in the development of the nervous system. Such genes can control the
acquisition of a pan-neuronal character, i.e. exit from the cell cycle and
neuronal differentiation, as well as the specification of particular neuronal
cell-types in vertebrates and invertebrates
(Bertrand et al., 2002).
Mash1 encodes a bHLH factor that controls important steps in
development of the nervous system. Mutation of Mash1 reduces
neurogenesis in the telencephalon (Casarosa
et al., 1999) and interferes with the differentiation of
sympathetic neurons (Guillemot et al.,
1993; Hirsch et al.,
1998; Sommer et al.,
1995). Conversely, mis-expression of Mash1 in the chick
spinal cord during the early developmental phase induces premature neuronal
differentiation of progenitor cells and the production of supernumerary
Isl1/2+ and Tlx3+ neurons (Müller et
al., 2005; Nakada et al.,
2004). Mash1 is expressed in progenitors of the dorsal
spinal cord and is essential for the development of the dorsal Tlx3+ neuronal
subtypes (dI3 and dI5) produced during the early developmental phase.
Asymmetric cell divisions occur during neuronal development in
invertebrates and vertebrates (Wodarz and
Huttner, 2003). Non-terminal asymmetric progenitor cell divisions
generate one progenitor and one differentiating neural cell. They allow
differentiation concomitant with the maintenance of the progenitor pool.
Asymmetric terminal divisions generate two different neural cells and have not
been assessed in the development of the vertebrate nervous system. Such
divisions have been extensively characterized in sensory organ development of
Drosophila (Lai and Orgogozo,
2004). The fact that dILA and dILB neurons arise in a
salt-and-pepper pattern raises the possibility that they are produced by
asymmetric terminal cell divisions. Using a Mash1GFP
allele in mice, we show that Mash1+ progenitors give rise to dILA and dILB
neurons. Furthermore, we demonstrate by retroviral tracing in the chick that a
single progenitor can give rise to dILA and dILB neurons, and that dILA
neurons are always the product of asymmetric cell divisions. Our analysis of
the Mash1–/– mice shows that in the absence of
Mash1, the generation of dILA neurons is severely impaired, which is
accompanied by the presence of supernumerary neural progenitors. By contrast,
development of dILB neurons is not affected in Mash1 mutant mice.
Thus, despite the fact that Mash1 is expressed in progenitors of dILA
and dILB neurons, it exerts its essential function only in the dILA lineage.
Mash1 appears thus to act in an asymmetric manner to coordinate cell cycle
exit and specification of the dILA daughter.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Parras et al., 2002). To
generate the Mash1GFP allele, Mash1-coding sequences were
replaced by Gap43-GFP cDNA (kindly provided by U. Mueller, The Scripps
Research Institute, La Jolla, CA) and a floxed neomycin (neoLoxP) cassette.
For this, a 3 kb fragment containing the Gap43-GFP sequence and neoLoxP was
amplified by PCR, and primers were used that also introduced in addition a
sequence of 45 nucleotides homologous to Mash1. We used homologous
recombination in bacteria to introduce into a 14 kb genomic subclone of Mash1
this Gap43-GFP neoLoxP fragment, which replaced the Mash1-coding sequence and
resulted in the Mash1GFPneoLoxP targeting vector
(Lee et al., 2001;
Yu et al., 2000). The sequence
of the GAP43-GFP fragment in the targeting vector was verified. E14.1 cells
were used to introduce the targeting vector by electroporation. ES cell
colonies that had inserted the targeting vector into their genome were
selected by G418 and analyzed for homologous recombination events by Southern
hybridization (Torres and Kühn,
1997). For removal of the neoLoxP cassette, the Cre-deleter strain
was used (Schwenk et al.,
1995); animals without a neo cassette (Mash1GFP allele)
were identified and used for further experiments. Routine genotyping was
performed by PCR; occasionally, genotypes were verified by Southern
hybridization. PCR-based genotyping for the Mash1GFP allele was
performed with the following primers:
5'-AAACCTCCCACACCTCCCCCTGAA-3' and 5'-ATGCCTCACCTCGACCTTCT
GCTC-3'.
The full-length mouse Mash1-coding sequence was cloned into the
pCIG vector (pCAGGS-IRES-nucEGFP) (cf.
Megason and McMahon, 2002).
The Ptf1a expression vector was a gift from Jane Johnson. These
vectors were electroporated unilaterally into the spinal cord of chick embryos
at a concentration of 1 µg/µl using a T820 electro-squareporator (BTX).
To determine the role of Mash1 and Ptf1a on neuronal
specification during the second developmental phase, the Mash1 and
Ptf1a expression constructs were electroporated at Hamburger Hamilton
stage (HH26) and the spinal cords were analyzed at HH29-30. Embryos that did
not express EGFP dorsally were excluded from the analysis. The effects of the
electroporated factors on neuronal specification were quantified as follows:
the numbers of Pax2+/GFP+, Tlx3+/GFP+ or Ptf1a+/GFP+ cells were determined on
the electroporated side of embryos. Furthermore, the absolute numbers of Pax2+
neurons were determined. A minimum of 10 sections from at least three
independently electroporated embryos were counted.
Production of replication-incompetent retrovirus, in ovo injection and lineage analysis
The avian replication-incompetent retroviral vector used, pRAVE GFPnLacZ (a
kind gift from M. Samson and C. Cepko), corresponds to a modified version of
pRAVE nLacZ (Peters and Cepko,
2002) and contains IRES-GFP. Viruses were pseudotyped with the
VSV-G envelope protein and produced in DF1 cells as previously described
(Chen et al., 1999). Fertilized
White Leghorn eggs (SPAFAS, CT) were used either at HH23-24 or at HH stages
25-26+. The lumen of the spinal cord was injected with RAVE GFPnLacZ virus,
and the embryos were analyzed at HH30-31. The rare clones derived from
infected cells were identified by anti-ß-galactosidase immunohistology,
and the cells were also analyzed for the expression of Lbx1 and Lhx1/5.
Embryos injected at HH 25-26+ were used for the analysis of the two-cell
clones. Progenitor cells were identified by the following criteria, location
in the ventricular zone of the dL domain and a lack of Lbx1 and Lhx1/5
expression. dILA and dILB neurons were identified by the expression of
Lbx1+/Lhx1/5+ and Lbx1+/Lhx1/5–, respectively, and by a location in the
mantle zone lateral of the dL domain. Clones containing cells whose identity
was ambiguous were discarded. Non-ambiguous clones were examined in 35 µm
frozen sections using a confocal microscope (LSM510, Zeiss). For this, stacks
of 0.84 µm optical sections were analyzed.
In situ hybridization, immunofluorescence, BrdU labeling and histology
For in situ hybridization, embryonic tissues were embedded into OCT
compound (Sakura) and cryosectioned. Hybridization was performed with
DIG-labeled riboprobes, many of which were generated from plasmids derived
from other laboratories (see acknowledgements).
Immunofluorescence staining was performed on 12 µm cryosections of mouse
and chick embryos fixed with 4% paraformaldehyde in 0.1 M sodium phosphate
buffer (pH 7.4). The following antibodies were used on mouse tissue: rabbit
and guinea-pig anti-Lbx1 (Müller et
al., 2002); rabbit and guinea-pig anti-Tlx3
(Müller et al., 2005);
rabbit anti-Olig3 (Müller et al.,
2005); mouse anti-Mash1 and anti-Ngn2 (David Anderson); guinea-pig
anti-Isl1 and guinea-pig anti-Lmx1b (Tom Jessell, Columbia University, New
York, USA); rabbit anti-Ngn1 (Jane Johnson); rabbit anti Gsh1/2 (Martin
Goulding); rabbit anti-Ptf1a (Helena Edlund); rabbit anti-GFP (Abcam); rabbit
anti-peripherin and mouse anti-NeuN (Chemicon); rabbit anti-Pax2 (Zymed);
rabbit anti ß-galactosidase (CAPPEL); mouse anti-Tuj1 (Babco); mouse and
rabbit anti-phospho-Histon3 (Upstate-Cell Signaling Solutions); monoclonal
mouse anti-Lhx1/5, anti-Pax6 and anti-Pax7 (Developmental Studies Hybridoma
Bank, University of Iowa). On chick tissue, the following antibodies were
used: rabbit anti-ß-galactosidase (CAPPEL); guinea-pig anti-Lbx1
(Müller et al., 2002);
monoclonal mouse anti-Lhx1/5 (Developmental Studies Hybridoma Bank, University
of Iowa); rabbit anti-Tlx3 (Müller et
al., 2005); rabbit anti-Pax2 (Zymed) and goat anti-GFP (Abcam). In
addition, various fluorophore-conjugated secondary antibodies (Dianova) were
employed. For amplification of weak signals, the TSA Cy3 System was used
(Perkin Elmer).
For BrdU labeling experiments, BrdU (Sigma; 75 µg/g body weight) was
injected intraperitoneally at various stages. Embryos were isolated at the
indicated times after injection. Sections were first treated with antibodies
that specifically detect various neuronal types and subsequently postfixed
(Müller et al., 2002).
Incorporated BrdU was then detected with either mouse (Sigma) or rat anti-BrdU
antibodies (Oxford Biotechnology). YO-PRO1 (Invitrogen) was used for nuclear
counterstaining. TUNEL assays were performed using the ApopTag fluorescein in
situ apoptosis detection kit (Intergen). Cell numbers for each genotype were
counted on confocal images, and at least nine sections from at least three
distinct animals were used for this.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Matise, 2002;
Müller et al., 2002). The
ratio of dILA to dILB neurons changes as development proceeds, but is constant
at a given developmental stage in different individuals
(Table 1). For example, pulse
chase experiments using BrdU indicate that at E12.5 the ratio of newborn dILA
to dILB neurons is 0.74±0.08. In the chick spinal cord, the dorsal
progenitor domain undergoes a similar change as development proceeds and
generates during a late phase dILA and dILB neurons, which also arise in a
salt-and-pepper pattern (data not shown). At HH30, the stage that is
comparable with E12.5 in mice, the ratio of newborn dILA to dILB neurons is
0.78±0.09, as assessed by BrdU pulse-chase experiments. The dL
progenitor domain in mouse and chick embryos expresses Mash1 and Gsh1/2
(Fig. 1E,F). Gsh1/2 is present
in all cells of the dL progenitor domain
(Fig. 1E,G,G'). By
contrast, Mash1 is expressed in some, but not all cells, of this domain, and
Mash1+ and Mash1– cells intermingle
(Fig. 1F,G,G'). Ptf1a
protein is expressed transiently, and is found in a subset of Mash1+
progenitors located in the lateral progenitor domain
(Fig. 1H, see also
Fig. 4L and
Fig. 7E-H), as well as in a
subset of dILA neurons located outside but close to the progenitor domain
(Fig. 1H'; see
Fig. 1I for a schematic display
of the neuronal subtype produced in the spinal cord at E12.5 and of the
progenitor domain that generates these neurons).
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dILA neurons are generated by asymmetric cell divisions
To assess whether single dorsal progenitor cells can give rise to one dILA
and one dLB neuron, we used retroviral lineage tracing in chick embryos and
infected progenitors with a replication incompetent RAVE-GFPnlacZ retrovirus
that expresses nuclear ß-galactosidase
[(Peters and Cepko, 2002), for
further details see Materials and methods]. Progenitor cells were infected at
stage HH25-26+, and the infected cells and their progeny were analyzed at
HH30-31 (Fig. 3). We analyzed
in detail only those clones that were located in or lateral to the dL domain,
and that contained two cells and at least one neuron. Thus, among 50
independently generated clones of this type, 23 contained one progenitor and
one neuron, and 27 contained two neurons
(Fig. 3B). These clones were
analyzed by immunohistological analysis, which demonstrated that dILA neurons
were generated by asymmetric cell divisions only (see
Fig. 3A for the types of cell
divisions observed). In particular, 60% of the dILA (Lbx1+/Lhx1/5+) neurons
were generated by cell divisions that produced one dILA neuron and one
progenitor, and 40% by cell divisions that produce one dILA and one dILB
neuron at this developmental stage (Fig.
3B-E). dILA neurons are therefore always the product of asymmetric
cell divisions, that can be terminal or non-terminal. By contrast, dILB
(Lbx1+/Lhx1/5–) neurons were produced by asymmetric and by symmetric
cell divisions (see Fig. 3A for
a summary of all observed divisions).
|
).
Histological and immunohistological analysis of the spinal cord indicated that
the domain occupied by differentiated neurons was reduced in size at E11.5 and
subsequent stages in Mash1–/– compared with
control mice (Fig. 4A,B;
Fig. 5A,B). By E12.5, this was
morphologically apparent by the abnormal triangular shape of the dorsal horn
of Mash1–/– mice (compare
Fig. 4A with 4B). BrdU-labeling
experiments indicated that the numbers of dILA neurons generated were severely
reduced in the Mash1–/– mice, whereas the
numbers of dILB neurons were not affected at E12.5
(Fig. 4A,B,D,E,G,H,I,K). Thus,
the dILA neuronal subtype generated by asymmetric cell divisions is the one
that is primarily affected by the Mash1 mutation. Ngn2
(Neurog2 – Mouse Genome Informatics), which encodes another
factor of the bHLH family, can replace neurogenic functions of Mash1
in the telencephalon and hindbrain of mutant mice
(Parras et al., 2002;
Pattyn et al., 2004); analysis
of Mash1Ngn2/Mash1Ngn2 mice, in which coding
sequences of Mash1 are substituted by Ngn2 cDNA,
demonstrated that Ngn2 was neither sufficient to rescue the change in the
ratio of dILA to dILB neurons, nor the deficit in neuron numbers
(Fig. 4A,C,D-G,H,J,K).
Ptf1a is known to be essential for the specification of dILA neurons
(Glasgow et al., 2005). We
also analyzed the expression of Ptf1a in the dorsal spinal cord of
Mash1–/– and
Mash1Ngn2/Mash1Ngn2 mice, which was markedly
reduced (Fig. 4L-O). Thus,
Mash1 is essential for Ptf1a expression, and Ngn2 cannot
rescue this. Hes5 or Dll1 expression was also reduced in the
dorsal spinal cord of Mash1 mutant mice, and expression of
Hes5 or Dll1 was rescued in the
Mash1Ngn2/Mash1Ngn2 animals
(Fig. 4P-R; data not
shown).
|
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Distinct expression of Mash1 and Ptf1a during the cell cycle
To identify if progenitor cells in a particular stage of their cell cycle
express Mash1 or Ptf1a, we labeled S-phase cells by injection of BrdU and
analyzed the BrdU+ cells at various time points (30 minutes, 2 hours and 8
hours) after the BrdU injections (Fig.
7). M-phase cells were identified by the immunohistological
analysis of phosphorylated histone 3. These labeling experiments indicated
that in the dorsal spinal cord at E12.5, the majority of the cells reach
M-phase 2 hours after the injection of BrdU
(Fig. 7A-D). The majority of
Ptf1a+ cells were BrdU+ only 8 hours after BrdU injections, and M-phase cells
never expressed Ptf1a (Fig.
7E-H). This indicates that Ptf1a is expressed mainly after the
M-phase and during the G0-phase of the cell cycle (see summary in
Fig. 7M). During the asymmetric
cell divisions that give rise to dILA neurons, Ptf1a expression is thus
induced after the division of the progenitor. This is consistent with the
observation that Ptf1a expression is restricted to the dILA lineage
(Glasgow et al., 2005). By
contrast, Mash1+ cells were BrdU+ at all time points after the BrdU
injections, and also M-phase cells were Mash1+
(Fig. 7I-L). Mash1 is therefore
expressed at all stages of the cell cycle in a subset of the progenitor cells,
and might mark progenitors that will undergo symmetric or asymmetric terminal
divisions (see summary in Fig.
7M). We propose therefore that during the asymmetric cell
divisions that generate dILA neurons, Mash1 acts after M-phase to
control Ptf1a expression and the correct specification of the dILA neuronal
subtype (see also Fig. 8B and
Discussion).
|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Notch
signals keep progenitors in an undifferentiated state and preclude neuronal
differentiation (Beatus and Lendahl,
1998; de la Pompa et al.,
1997; Hatakeyama et al.,
2004; Hitoshi et al.,
2002; Ohtsuka et al.,
1999). To overcome the increased Notch signals, the pro-neural
functions of factors like Mash1 might thus gain in importance. Mash1 and Ngn2
can both act as pro-neural factors (Parras
et al., 2002), and both induce premature neuronal differentiation
when mis-expressed in the chick (Cai et
al., 2000; Lee et al.,
2005; Lee and Pfaff,
2003; Mizuguchi et al.,
2001; Nakada et al.,
2004). In the dorsal spinal cord, aspects of the proneural
function of Mash1 can be rescued by the expression of Ngn2;
for example, the expression of Hes5 or Dll1. Nevertheless,
Ngn2 cannot rescue the deficits in dorsal neuron numbers that are
caused by the Mash1 mutation. The reduction in the neuronal differentiation in Mash1 mutant mice became apparent around E11.5 and thus around the time when the late phase of neurogenesis commences and dILA and dILB neuronal subtypes appear. Interestingly, the Mash1 mutation only reduced the numbers of dILA neurons, whereas the numbers of dILB neurons generated were not affected at E12.5. We demonstrate that this reflects a reduced probability of differentiation, which was accompanied by an increased cell number in the dorsal progenitor zone of Mash1–/– animals. The number of cells that incorporate BrdU increased proportionally with the cell numbers, indicating that the supernumerary cells can replicate their DNA and correspond thus to progenitors. Nevertheless, some progenitor cells that inappropriately failed to differentiate in Mash1 mutant mice might not have retained a complete progenitor character, as many Lbx1+ cells are detected in the progenitor zone of Mash1 mutant mice. These abnormal progenitors express Lbx1, but not other markers of neuronal differentiation. The increase in cell number in the progenitor zone of the dorsal spinal cord of Mash1 mutant mice is accompanied by an increase in apoptosis, and we suggest that many supernumerary progenitors are subsequently eliminated by cell death (see Fig. 8A for a summary).
|
).
Mis-expression experiments assign instructive functions to Mash1
during early development in the specification of dI3 and dI5 neurons.
Nevertheless, Mash1 imposes only a partial dI3 or dI5 character, and
the activity of additional factors is required for correct specification of
these neurons (Helms et al.,
2005; Müller et al.,
2005; Nakada et al.,
2004). Our previous work has identified one such factor, Olig3,
that can cooperate with Mash1 to specify dI3 neurons
(Müller et al., 2005),
but we have to postulate others that are involved in order to explain the
observed effects of Mash1 on the specification of dI5 neurons.
|
).
Mash1 appears to direct the specification dILA, but not dI4 neurons,
via controlling Ptf1a (see Fig.
8B for a summary). However, electroporation experiments indicate
that Mash1 is not sufficient to induce Ptf1a expression, and we have
to postulate an as yet unknown cooperating factor.
Two possible models can account for the function of Mash1 in development of
dILA and dILB neurons. In the first model, Mash1 would be required for cell
cycle exit of all neurons. In addition, in the asymmetric divisions that
generate dILA neurons, Mash1 would be essential for specification of the dILA
daughter. This would account for the reduction in the number of neurons in the
Mash1–/– mice, and we would have to postulate
that aberrantly specified dILA neurons would assume a dILB fate. In such a
scenario, a mere coincidence would account for the unchanged number of dILB
neurons observed in control and Mash1 mutant mice at E12.5. Ngn2
would be expected to rescue, at least partially, cell cycle exit and the
number of dorsal neurons in Mash1 mutant mice, but not the deficit in
neuronal specification (Parras et al.,
2002; Pattyn et al.,
2004). This should cause an increase in dILB neurons in
Mash1Ngn2/Mash1Ngn2 compared with
Mash1–/– mice, which was not observed. We
therefore favor a second model, in which Mash1 exerts a function in
cell cycle exit only if the progenitor produces a daughter destined to a dILA
fate. Thus, in asymmetric divisions that generate dILA neurons, Mash1
(but not Ngn2) would coordinate cell cycle exit and specification of
the one daughter destined to generate a dILA neuron (see
Fig. 8 for a summary of the
second model). Notch signals control asymmetric cell divisions and the
asymmetric fate specification in neural development of Drosophila
(Lai and Orgogozo, 2004). It
remains to be investigated if Notch is required, together with
Mash1, in the asymmetric cell divisions that generate dILA
neurons.
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ACKNOWLEDGMENTS |
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N), and to express Ptf1a. By contrast, Mash1 is dispensable
for the development of the dILB lineage.