1 Center for Basic Neuroscience, University of Texas Southwestern Medical
Center, Dallas, TX 75390, USA
2 Molecular Biology Department, University of Texas Southwestern Medical Center,
Dallas, TX 75390, USA
3 Department of Cell and Developmental Biology, and Program in Developmental
Biology, Vanderbilt University School of Medicine, Nashville, TN 37232,
USA
* Author for correspondence (e-mail: jane.johnson{at}utsouthwestern.edu)
Accepted 13 October 2005
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SUMMARY |
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Key words: Spinal cord development, Dorsal horn inhibitory neurons, BHLH transcription factor, Mouse
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Introduction |
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In addition to expression in the pancreas and developing cerebellum, Ptf1a
is present in the dorsal neural tube of early stage embryos
(Obata et al., 2001), an
embryonic structure that gives rise to the dorsal horn of the spinal cord in
the mature animal. The spinal cord dorsal horn largely consists of excitatory
(glutamatergic) and inhibitory (GABAergic) neurons that modulate somatosensory
inputs from the periphery, including pain, temperature and mechanoception.
Distinct neuronal subtypes in the developing dorsal neural tube have been
defined by the timing of their birth, and key differences in the expression of
homeodomain (HD) transcription factors
(Jessell, 2000
). The
requirement for bHLH transcription factors, Math1 (Atoh1 - Mouse Genome
Informatics), Ngn1, Ngn2, Mash1 (Ascl1 - Mouse Genome Informatics) and Olig3,
for the formation of specific neuronal subtypes defined by the HD factors has
been demonstrated (Bermingham et al.,
2001
; Gowan et al.,
2001
; Helms et al.,
2005
; Müller et al.,
2005
), but their roles in specifying neurotransmitter identity
have not been reported. Rather, the HD genes are involved in generating
glutamatergic versus GABAergic neurons in the dorsal horn. Tlx1 and
Tlx3 have been shown to be post-mitotic selector genes for the
glutamatergic transmitter phenotype (Cheng
et al., 2004
). In the dorsal horn of Tlx1/3 double
mutants, glutamatergic neurons are reduced while GABAergic neurons are
increased. By contrast, no selector gene has been described for the GABAergic
phenotype, although HD factors Lbx1 and Pax2 play roles in generating
GABAergic neurons in the dorsal horn (Cheng
et al., 2005
; Cheng et al.,
2004
; Gross et al.,
2002
; Müller et al.,
2002
).
Here we report that, in the neural tube, Ptf1a is required for dorsal
neural tube Pax2 expression and suppression of Tlx3, which leads to the
formation of GABAergic neurons while suppressing the formation of
glutamatergic neurons. Thus, Ptf1a and Tlx1/3 act as opposing switches for the
generation of neurons with specific neurotransmitter phenotypes, revealing
genetic interactions that link the development of these two classes of
interneurons in the spinal cord. A disruption in the balance between
inhibitory and excitatory neuronal activity of the magnitude that occurs in
the absence of Ptf1a function has profound consequences for the organism, and
may explain the respiratory difficulties and cerebral excitability seen in
humans with a mutation in this gene
(Hoveyda et al., 1999;
Sellick et al., 2004
).
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Materials and methods |
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X-gal staining
Embryos were fixed for 1 hour in 4% formaldehyde in 0.1 mol/l sodium
phosphate buffer pH 7.4 at room temperature and washed three times in 0.1
mol/l sodium phosphate buffer pH 7.4 for 30 minutes each. Embryos were
incubated at 30°C for 24 hours in X-gal staining solution (PBS/5 mmol/l
potassium ferricyanide, 5 mmol/l potassium ferrocyanide, 2 mmol/l
MgCl2, 1 mg/ml X-gal), washed three times in 0.1 mol/l sodium
phosphate buffer pH 7.4 and whole-mount images were taken; then the embryos
were sunk in 30% sucrose in 0.1 mol/l sodium phosphate buffer pH 7.4 overnight
at 4°C, embedded in OCT, and cryosectioned at 40 µm. Adult mice were
perfused with 4% formaldehyde in 0.1 mol/l sodium phosphate buffer pH 7.4
under standard conditions. Brains and spinal cords were fixed for an
additional 2 hours at 4°C and processed as above for cryosection at 20
µm. Sections were incubated in X-gal solution, rinsed and counterstained
with Nuclear Fast Red or Nissl.
Immunofluorescence and mRNA in-situ hybridization
Appropriately staged embryos were dissected in ice-cold 0.1 mol/l sodium
phosphate buffer pH 7.4 and fixed for 2 hours at 4°C in 4% formaldehyde in
0.1 mol/l sodium phosphate buffer pH 7.4. Embryos were processed as above for
cryosection at 30 µm.
Immunofluorescence was performed using the following primary antibodies:
Mouse anti-BrdU (Becton Dickinson), guinea pig anti-VGLUT2 (Chemicon), mouse
anti-Lhx1/5 (4F2) (Developmental Studies Hybridoma Bank), rabbit anti-Ptf1a
(Li and Edlund, 2001), mouse
anti-Mash1 (Lo et al., 1991
),
rabbit anti-GFP (Molecular Probes), chicken anti-GFP (Chemicon), guinea pig
anti-Lmx1b (Müller et al.,
2002
), mouse anti-GAD67 (Sigma), rabbit anti-Islet1/2
(Tsuchida et al., 1994
),
rabbit anti-Pax2 (Zymed), rabbit anti-Tlx3 (gift from T. Müller and C.
Birchmeier), and mouse anti-GABA (Sigma). For BrdU experiments, BrdU (200
µg/g body weight) was injected into pregnant mothers for 1 hour before
sacrifice. Double immunofluorescence of Ptf1a and BrdU was performed
sequentially with Ptf1a antibodies followed by treatment of the sections with
2N HCl for 15 minutes, 0.1 mol/l sodium borate pH 8.5 for 20 minutes, and
incubation with primary BrdU. Specific neuronal cell types were counted using
confocal (Bio-Rad MRC 1024) images from a minimum of three different animals
on three or more sections. mRNA in-situ hybridization was carried out as
described (Birren et al., 1993
;
Cheng et al., 2004
). Antisense
probes were made from plasmids provided by Q. Ma
(Cheng et al., 2004
). All
sections shown are from the forelimb level.
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Results |
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Ptf1a is restricted to post-mitotic cells within the ventricular zone of the dorsal neural tube in an overlapping pattern with Mash1
The ß-gal staining in the dorsal neural tube resembled the expression
pattern of another bHLH transcription factor, Mash1
(Gowan et al., 2001;
Helms et al., 2005
). To
characterize the expression pattern of Ptf1a in more detail in this
region, we used double label immunofluorescence with rabbit anti-Ptf1a
(Li and Edlund, 2001
) and
mouse anti-Mash1 (Lo et al.,
1991
), or mouse anti-BrdU in BrdU-pulsed embryos. At E10.5, Ptf1a
was detected within the central portion of the dorsal Mash1 domain
(Fig. 1G). In this region,
Mash1 levels were low relative to levels in adjacent dorsal and ventral
regions (Fig. 1G). Because
Mash1 is present in ventricular zone cells adjacent to dI3-dI5 neurons
(Helms et al., 2005
), this
pattern suggests that Ptf1a may be in the dI4 precursor domain. Within the
domain common to both factors, Ptf1a and Mash1 co-labeled a subset of cells
located on the ventricular side (Fig.
1G, inset). The pattern of Ptf1a is dynamic, and by E11.5 the
dorsal and ventral boundaries of Ptf1a became identical with those of Mash1
(Fig. 1I). At this stage of
neural tube development, the dorsal ventricular zone gives rise to the two
late-born neurons, dILA and dILB. Ptf1a marks cells that
appear to have exited the cell cycle, as they rarely co-label with BrdU
incorporation at either E10.5 or 11.5 (Fig.
1H,J). This cell-cycle status of Ptf1a cells contrasts to the
Mash1 population, in which a significant proportion of cells are still
dividing (Helms et al., 2005
).
Taken together, Ptf1a is largely restricted to post-mitotic cells in the
ventricular zone of the dorsal neural tube in a pattern that suggests it may
be in the precursors to dI4, dILA and/or dILB
neurons.
|
In the Ptf1a null mutant embryos, the number of cells increased in
the dI5 cells complemented the number of dI4 neurons lost
(Fig. 2J). These results
suggest that in the absence of Ptf1a, the dI4 cells trans-fate into dI5. To
test this directly, we crossed the Ptf1aCre/+ mice to the
R26R-stop-YFP Cre reporter strain, which will express YFP in cells
with Cre recombinase and in all descendants of these cells
(Srinivas et al., 2001). In
Ptf1aCre/+;R26R-stop-YFP+/- mice, the dI4
marker Lhx1/5 co-localized with YFP, demonstrating that dI4 neurons are
derived from Ptf1a precursor cells, and thus, the loss of dI4 neurons in the
Ptf1a null embryos is cell-autonomous (Fig.
2E,F). In these embryos, YFP did not co-label with the dI5 marker
Lmx1b (Fig. 2G). By contrast,
in Ptf1aCre/Cre;R26R-stop-YFP+/- embryos, the
dI4 neurons were lost and YFP now co-localized with Lmx1b (dI5)
(Fig. 2G,H). Thus, in the
absence of Ptf1a, the cell generates a dI5 neuron rather than a dI4.
At all stages examined, YFP expression was higher in the Ptf1a mutant than in the Ptf1a heterozygous embryos. This is at least partly due to the presence of two Cre alleles in Ptf1aCre/Cre versus one allele in Ptf1aCre/+. However, it could also reflect a component of a negative feedback loop in the regulation of the Pft1a locus.
Ptf1a is required to generate late-born dILA and to suppress dILB interneurons
A second round of neurogenesis occurs in the developing spinal cord between
E11 and E13 to form the dILA and dILB populations of
dorsal interneurons (Gross et al.,
2002; Müller et al.,
2002
). The Ptf1a mutants were examined at E12.5 with Pax2
and Lhx1/5, which mark dILA, and Lmx1b and Tlx3, which mark
dILB, to determine if these two late-born populations require
Ptf1a. In the absence of Ptf1a, Pax2 was completely lost and Lhx1/5 was
dramatically reduced, specifically in the dorsal half of the neural tube,
revealing a loss of dILA neurons
(Fig. 3A,B). The number of
cells expressing Lmx1b or Tlx3 (dILB) was significantly increased
in the absence of Ptf1a, while cells expressing Isl1 were unaffected
(Fig. 3C,D,I,J; see
Fig. 3K for cell counts). No
increase in cell death was detected using TUNEL or Caspase3
immunocytochemistry at this stage (data not shown). These results demonstrate
that Ptf1a is required for the formation of dILA neurons and
normally suppresses the formation of dILB neurons.
|
|
Although the level of Ptf1a decreased by E16.5, we were able to use Ptf1aCre;R26R-stop-YFP embryos to map the fate of Ptf1a-expressing cells into E16.5 dorsal horns to verify that the loss of GABAergic neurons is cell-autonomous. The vast majority of YFP in Ptf1aCre/+;R26R-stop-YFP+/- embryos was restricted to the dorsal spinal cord at E16.5 (Fig. 4C). Co-localization of YFP with GAD67 and GABA indicated that the loss of GABAergic neurons in Ptf1a-deficient embryos is at least in part a cell-autonomous effect as expected (Fig. 4E,G). These co-localization experiments are not as clear as the analysis with the transcription factor markers at earlier stages, because the neurotransmitter proteins tend to localize in the distal processes of the neurons, while the YFP is mainly cytoplasmic with some signal reaching distal processes. In Fig. 4E, arrows indicate regions outside the cell body where YFP and GAD67 co-localized. GABA is easier to detect in cell bodies, and thus the overlap with YFP is clearer (Fig. 4G, arrows). It is also important to note that the in-vivo recombination system used here to trace the lineage of Ptf1a cells is not 100% efficient and is not expected to indicate every Ptf1a descendent. Regardless, this analysis together with experiments described in Fig. 3 demonstrate that Ptf1a is in cells fated to become GABAergic neurons of the dorsal horn and that it is essential for this neuronal subtype to form.
YFP in Ptf1aCre/Cre;R26R-stop-YFP+/- embryos, which are deficient in Ptf1a, was also largely restricted to the dorsal horn, but it was detected in more cells and encompassed a broader medial-lateral area compared with heterozygous embryos (Fig. 4C,D). Besides suggesting that Ptf1a may normally be in a negative autoregulatory loop, the aberrant location of YFP-labeled cells on the lateral edges that appear to stream ventrally are consistent with mis-specification of neuronal subtype in the mutant.
Ptf1a suppresses glutamatergic neuronal differentiation in the dorsal horn
In the absence of Ptf1a there was a neuronal subtype switch from
dI4/dILA to dI5/dILB (Figs
2,
3). dILB neurons
form the glutamatergic neurons in the dorsal horn
(Cheng et al., 2004). To
determine if the aberrantly formed dILB neurons continue to mature
with glutamatergic characteristics, we examined Ptf1a mutant embryos
for vesicular glutamate transporter2 (VGLUT2) and glutamate receptor
(GluR2/3). mRNA in-situ hybridization and immunofluorescence demonstrated an
increase of VGLUT2 and GluR2/3 in the dorsal horn of
Ptf1aCre/Cre embryos at E16.5, when compared with
Ptf1aCre/+ embryos
(Fig. 5A-D, and data not
shown). This increase was clearly indicated by an increase in VGLUT2 in the
more superficial laminae, as indicated by the arrows in
Fig. 5C,D. Likewise, an
increase in the density of Tlx3-expressing cells was also seen at E16.5
(Fig. 5G,H), consistent with
the importance of Tlx1/3 in the generation of dorsal horn glutamatergic
neurons (Cheng et al., 2004
).
By contrast, no increase was detected in the glycinergic neuronal marker GlyT2
by mRNA in-situ hybridization (data not shown).
Just as at the earlier embryonic stages, we examined Ptf1aCre/+;R26R-stop-YFP+/- and Ptf1aCre/Cre;R26R-stop-YFP+/- embryos for co-localization of VGLUT2 with YFP to address the question of a neurotransmitter fate switch of the Ptf1a mutant cells. Significant co-expression of VGLUT2 with YFP was observed only in the Ptf1a null embryos (Fig. 5E,F). As with the GABAergic markers, the co-localization of VGLUT2 with YFP has caveats due to the enrichment of VGLUT2 in distal processes. However, taken together with the loss of Pax2 expression and increase in Tlx3, these results demonstrate that Ptf1a functions as a switch; it is required for the generation of GABAergic neurons and suppresses generation of glutamatergic neurons in the dorsal horn of the spinal cord (Fig. 5I).
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Discussion |
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GABAergic and glutamatergic neurons appear to be alternative fate choices
in the dorsal neural tube, and their development is genetically linked through
the function of transcription factors such as Ptf1a, Tlx1/3, Lbx1 and Pax2
(Cheng et al., 2005;
Cheng et al., 2004
;
Gross et al., 2002
;
Müller et al., 2002
).
Recently it was proposed that the HD transcription factors Tlx1 and Tlx3 are
selector proteins biasing choice of glutamatergic over GABAergic cell fates
(Cheng et al., 2004
). This may
at least be in part due to their inhibition of Pax2 expression, as
Pax2 is required for the formation of GABAergic neurons in the dorsal horn,
and in the Tlx1/3 double mutant, Pax2 is dramatically increased
(Cheng et al., 2004
). Pax2 does
not appear to have selector function, as there is no concomitant increase in
glutamatergic neurons in Pax2 null embryos
(Cheng et al., 2004
). Another
HD factor, Lbx1, is also required for generating the correct numbers of
GABAergic neurons (Cheng et al.,
2005
; Gross et al.,
2002
; Müller et al.,
2002
). Recently, the suppression of Lbx1 activity by Tlx3 has been
suggested as a mechanism for selecting dorsal horn glutamatergic cell fate
(Cheng et al., 2005
). Results
presented here demonstrate that Ptf1a is largely in post-mitotic cells in the
dorsal neural tube. Therefore, Ptf1a has selector function opposite to Tlx1/3;
it is required for the generation of dI4 and dILA fates, which
mature into GABAergic neurons, and it suppresses the alternative fates, dI5
and dILB, which form glutamatergic neurons
(Fig. 5I). The function of
Ptf1a in switching cell fates in the dorsal spinal cord is similar to the role
attributed to Ptf1a in pancreatic development. Inactivation of Ptf1a switches
progenitor cells from pancreatic lineages to duodenal lineages
(Kawaguchi et al., 2002
).
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Ptf1a is a Twist-like bHLH factor that can heterodimerize with E-proteins
such as E47, and bind e-box containing DNA
(Beres et al., 2005;
Obata et al., 2001
). However,
it is unique in the bHLH family in that it also directly interacts with
Rbpsuh, a transcriptional effector of the Notch signaling pathway, to bind a
combined e-box;T/C box containing DNA sequence
(Beres et al., 2005
;
Obata et al., 2001
). Evidence
from Beres et al. (Beres et al.,
2005
) suggests that the interaction site of Rbpsuh with Ptf1a
overlaps that of Rbpsuh with Notch intracellular domain. Thus, the timer,
Ptf1a;E-protein:Rbpsuh, reveals a Notch-independent Rbpsuh mechanism of
action. These different protein-protein and protein-DNA interactions suggest a
variety of mechanisms of action for Ptf1a, including many of those mechanisms
previously described for selector gene function
(Mann and Carroll, 2002
). For
example, similar to Twist function, heterodimerization with E-proteins could
sequester this shared partner from other class A bHLH factors such as Mash1.
Depending on the transcriptional activity of these different heterodimers, the
consequence could be either an increase or decrease in specific target
expression (Obata et al.,
2001
). Furthermore, by forming a trimer with Rbpsuh and E-protein
(Beres et al., 2005
), this
complex not only has altered DNA target recognition, but may also directly
impact Notch signaling by competing for use of the Rbpsuh subunit. Combining
these different protein-protein interactions together with complex arrangement
of cis-elements on transcriptional targets, makes Ptf1a a crucial component
for the intricate interactions required for generating the appropriate number
of specific neuronal cell-types.
Overexpression of Ptf1a, or a DNA-binding mutant of Ptf1a, in the chick
neural tube resulted in excess Lhx1/5+ cells (dI2-like) (data not
shown). This phenotype is probably due to sequestering E-protein, as
co-expressing E47 with Ptf1a suppressed this phenotype (data not shown). The
possible competing roles for Ptf1a in different complexes, such as the
heterodimer with E-proteins versus the heterotrimer with E-protein and RbpsuH,
make overexpression paradigms difficult to interpret. Even so, mis-expression
of Ptf1a in the dorsal telencephalon conferred a GABAergic phenotype to the
newly forming neurons (Hoshino et al.,
2005), supporting a role for Ptf1a in determining GABAergic
neuronal cell fates.
Ptf1a is not required for all GABAergic neurons in the nervous system. Its
expression is restricted to a subset of cells in the developing diencephalon,
hindbrain and spinal cord. In Ptf1a mutant embryos, cells expressing
GABAergic markers remain, as is seen in the ventral spinal cord
(Fig. 4B). Two other bHLH
transcription factors, Mash1 and Heslike (also known as Helt), have been shown
to mediate GABAergic fate in the telencephalon
(Fode et al., 2000;
Miyoshi et al., 2004
). Mash1
has overlapping expression with Ptf1a in the dorsal neural tube but it is
Ptf1a and not Mash1 that is required for the GABAergic phenotype in the spinal
cord. Thus, different bHLH factors are required for GABAergic neurons in
different regions of the nervous system. It remains to be determined whether
Ptf1a codes for shared characteristics in GABAergic neurons in the dorsal horn
of the spinal cord and in the cerebellum, in addition to the neurotransmitter
phenotype, that are distinct from those in GABAergic neurons derived from
Mash1-expressing cells in the telencephalon.
Dramatic phenotypes have been detected in the development of the pancreas
(Kawaguchi et al., 2002), the
cerebellum (Sellick et al.,
2004
) and the dorsal spinal cord (this manuscript). In pancreas,
there is almost a complete loss of islet and exocrine tissue. The requirement
for Ptf1a for generation of multiple GABAergic interneurons in the cerebellum
and deep cerebellar nuclei, including Purkinje, stellate, basket and Golgi
cells, is responsible for the cerebellar agenesis
(Hoshino et al., 2005
).
Phenotypes in these two tissues also occur in humans with a truncation in the
PTF1A gene (Sellick et al.,
2004
). As shown here, the Ptf1a null mouse develops a
dorsal spinal cord with nearly a complete loss of inhibitory GABAergic neurons
with an increase in glutamatergic neurons. This excess in excitatory neurons
unopposed by inhibitory neurons may explain the irregular respiratory patterns
and increased cerebral excitability in human patients with mutations in
Ptf1a (Hoveyda et al.,
1999
). Given the absolute requirement for Ptf1a for the formation
of the cell types studied so far, it is likely that additional neurons in the
brainstem and the ventral hypothalamus, two other domains of Ptf1a
expression, are mis-specified in the mutant as well.
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ACKNOWLEDGMENTS |
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Artavanis-Tsakonas, S., Rand, M. D. and Lake, R. J.
(1999). Notch signaling: cell fate control and signal integration
in development. Science
284,770
-776.
Beres, T., Masui, T., Swift, G. H., Shi, L., Henke, R. M. and MacDonald, R. J. (2005). PTF1: an organ-specific and Notch-independent bHLH complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue RBP-L. Mol. Cell. Biol. (in press).
Bermingham, N. A., Hassan, B. A., Wang, V. Y., Fernandez, M., Banfi, S., Bellen, H. J., Fritzsch, B. and Zoghbi, H. Y. (2001). Proprioceptor pathway development is dependent on Math1. Neuron 30,411 -422.[CrossRef][Medline]
Bertrand, N., Castro, D. S. and Guillemot, F. (2002). Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci. 3, 517-530.[CrossRef][Medline]
Birren, S. J., Lo, L. and Anderson, D. J.
(1993). Sympathetic neuroblasts undergo a developmental switch in
trophic dependence. Development
119,597
-610.
Bray, S. and Furriols, M. (2001). Notch pathway: Making sense of Suppressor of hairless. Curr. Biol. 11,R217 -R221.[CrossRef][Medline]
Caspary, T. and Anderson, K. V. (2003). Patterning cell types in the dorsal spinal cord: what the mouse mutants say. Nat. Rev. Neurosci. 4,289 -297.[CrossRef][Medline]
Cheng, L., Arata, A., Mizuguchi, R., Qian, Y., Karunaratne, A., Gray, P. A., Arata, S., Shirasawa, S., Bouchard, M., Luo, P. et al. (2004). Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat. Neurosci. 7,510 -517.[CrossRef][Medline]
Cheng, L., Abdel-Samad, O., Xu, Y., Mizuguchi, R., Luo, P., Shirasawa, S., Goulding, M. and Ma, Q. (2005). Lbx1 and Tlx3 act as opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nat. Neurosci. 8,1510 -1515.[CrossRef][Medline]
Cockell, M., Stevenson, B. J., Strubin, M., Hagenbuchle, O. and Wellauer, P. K. (1989). Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the acinar pancreas. Mol. Cell. Biol. 9,2464 -2476.[Medline]
Fode, C., Ma, Q., Casarosa, S., Ang, S.-L., Anderson, D. J. and
Guillemot, F. (2000). A role for neural determination genes
in specifying the dorsoventral identity of telencephalic neurons.
Genes Dev. 14,67
-80.
Gowan, K., Helms, A. W., Hunsaker, T. L., Collisson, T., Ebert, P. J., Odom, R. and Johnson, J. E. (2001). Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31,219 -232.[CrossRef][Medline]
Gross, M. K., Dottori, M. and Goulding, M. (2002). Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34,535 -549.[CrossRef][Medline]
Helms, A. W. and Johnson, J. E. (2003). Specification of dorsal spinal cord interneurons. Curr. Opin. Neurobiol. 13,42 -49.[CrossRef][Medline]
Helms, A. W., Battiste, J., Henke, R. M., Nakada, Y., Simplicio,
N., Guillemot, F. and Johnson, J. E. (2005). Sequential roles
for Mash1 and Ngn2 in the generation of dorsal spinal cord interneurons.
Development 132,2709
-2719.
Hoshino, M., MNakamura, S., Mori, K., Kawauchi, T., Terao, M., Nishimura, Y., Fukuda, A., Fuse, T., Matsuo, N., Sone, M. et al. (2005). Ptf1a, a bHLH Transcriptional Gene, Defines GABAergic Neuronal Fates in Cerebellum. Neuron 47,201 -213.[CrossRef][Medline]
Hoveyda, N., Shield, J. P., Garrett, C., Chong, W. K.,
Beardsall, K., Bentsi-Enchill, E., Mallya, H. and Thompson, M. H.
(1999). Neonatal diabetes mellitus and cerebellar
hypoplasia/agenesis: report of a new recessive syndrome. J. Med.
Genet. 36,700
-744.
Ibuki, T., Hama, A. T., Wang, X. T., Pappas, G. D. and Sagen, J. (1997). Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 76,845 -858.[CrossRef][Medline]
Jessell, T. M. (2000). Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genetics 1,20 -29.[CrossRef][Medline]
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J. and Wright, C. V. E. (2002). The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genetics 32,128 -134.[CrossRef][Medline]
Krapp, A., Knofler, M., Ledermann, B., Burki, K., Berney, C.,
Zoerkler, N., Hagenbuchle, O. and Wellauer, P. K. (1998). The
bHLH protein PTF1-p48 is essential for the formation of the exocrine and the
correct spatial organization of the endocrine pancreas. Genes
Dev. 12,3752
-3763.
Kriks, S., Lanuza, G. M., Mizuguchi, R., Nakafuku, M. and
Goulding, M. (2005). Gsh2 is required for the repression of
Ngn1 and specification of dorsal interneuron fate in the spinal cord.
Development 132,2991
-3002.
Lee, S. K. and Pfaff, S. L. (2001). Transcriptional networks regulating neuronal identity in the developing spinal cord. Nat. Neurosci. 4,1183 -1191.[CrossRef][Medline]
Li, H. and Edlund, H. (2001). Persistent expression of Hlxb9 in the pancreatic epithelium impairs pancreatic development. Dev. Biol. 240,247 -253.[CrossRef][Medline]
Liu, Y., Helms, A. W. and Johnson, J. E.
(2004). Distinct activities of Msx1 and Msx3 in dorsal neural
tube development. Development
131,1017
-1028.
Lo, L.-C., Johnson, J. E., Wuenschell, C. W., Saito, T. and Anderson, D. J. (1991). Mammalian achaete-scute homolog 1 is transiently expressed by spatially-restricted subsets of early neuroepithelial and neural crest cells. Genes Dev. 5,1524 -1537.[Abstract]
Mann, R. S. and Carroll, S. B. (2002). Molecular mechanisms of selector gene function and evolution. Curr. Opin. Genet. Dev. 12,592 -600.[CrossRef][Medline]
Miyoshi, G., Bessho, Y., Yamada, S. and Kageyama, R.
(2004). Identification of a novel basic helix-loop-helix gene,
Heslike, and its role in GABAergic neurogenesis. J.
Neurosci. 24,3672
-3682.
Müller, T., Brohmann, H., Pierani, A., Heppenstall, P. A., Lewin, G. R., Jessell, T. M. and Birchmeier, C. (2002). The homeodomain factor Lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34,551 -562.[CrossRef][Medline]
Müller, T., Anlag, K., Wildner, H., Britsch, S., Treier, M.
and Birchmeier, C. (2005). The bHLH factor Olig3 coordinates
the specification of dorsal neurons in the spinal cord. Genes
Dev. 19,733
-743.
Obata, J., Yano, M., Mimura, H., Goto, T., Nakayama, R., Mibu,
Y., Oka, C. and Kawaichi, M. (2001). p48 subunit of mouse
PTF1 binds to RBP-Jk/CBF-1, the intracellular mediator of Notch signalling,
and is expressed in the neural tube of early stage embryos. Genes
Cells 6,345
-360.
Rose, S. D., Swift, G. H., Peyton, M. J., Hammer, R. E. and
MacDonald, R. J. (2001). The role of PTF1-P48 in pancreatic
acinar gene expression. J. Biol. Chem.
276,44018
-44026.
Rudomin, P. and Schmidt, R. F. (1999). Presynaptic inhibition in the vertebrate spinal cord revisited. Exp. Brain Res. 129,1 -37.[CrossRef][Medline]
Sellick, G. S., Barker, K. T., Stolte-Dijkstra, I., Fleischmann, C., Coleman, R. J., Garrett, C., Gloyn, A. L., Edghill, E. L., Hattersley, A. T., Wellauer, P. K. et al. (2004). Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat. Genet. 36,1301 -1305.[CrossRef][Medline]
Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70-71.[CrossRef][Medline]
Srinivas, S., Watanabe, T., Lin, C. S., William, C. M., Tanabe, Y., Jessell, T. M. and Costantini, F. (2001). Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1,4 .[CrossRef][Medline]
Tsuchida, T., Ensini, M., Morton, S. B., Baldassare, M., Edlund, T., Jessell, T. M. and Pfaff, S. L. (1994). Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79,957 -970.[CrossRef][Medline]
Wiesenfeld-Hallin, Z., Aldskogius, H., Grant, G., Hao, J. X., Hokfelt, T. and Xu, X. J. (1997). Central inhibitory dysfunctions: mechanisms and clinical implications. Behav. Brain Sci. 20,420 -425; discussion 435-513.[CrossRef][Medline]
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