Previous Article | Next Article 
Molecular and Cellular Biology, July 2001, p. 4399-4403, Vol. 21, No. 13
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.13.4399-4403.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Mice Lacking the Nkx6.2 (Gtx)
Homeodomain Transcription Factor Develop and Reproduce
Normally
Jun
Cai,
Yingchuan
Qi,
Rui
Wu,
Geoffrey
Modderman,
Hui
Fu,
Rugao
Liu, and
Mengsheng
Qiu*
Department of Anatomical Sciences and
Neurobiology, School of Medicine, University of Louisville,
Louisville, Kentucky 40292
Received 5 February 2001/Accepted 23 March 2001
 |
ABSTRACT |
The Nkx homeobox genes are expressed in a variety of
developing tissues and have been implicated in controlling tissue
patterning and cell differentiation. Expression of Nkx6.2
(Gtx) was previously observed in the embryonic neural tube,
testis, and differentiating oligodendrocytes. To investigate the role
of Nkx6.2 in the control of cell specification and
differentiation, we generated mice with null mutations in
Nkx6.2 using the standard gene targeting approach. Null
mutant mice were viable and fertile without apparent histological and
immunohistochemical changes in the central nervous systems and testis.
The absence of detectable phenotypes suggests a redundant function of
Nkx6.2 in mouse development.
| |
INTRODUCTION |
Nkx6.2 was originally
identified as a novel homeobox gene that was specifically expressed in
brain glial cells and testis germ cells (Gtx)
(8). Subsequent studies by Awatramani et al. (1) had demonstrated that Gtx expression in
glial cells was restricted in differentiated, postmitotic
oligodendrocytes but not in oligodendrocyte precursor cells or
astrocytes. The expression of Gtx in maturing
oligodendrocytes had been suggested to regulate oligodendrocyte
myelination. Recently, we renamed Gtx as Nkx6.2 based on its high degree of sequence homology to the Nkx6.1
homeobox gene, including a nearly identical homeodomain and a
characteristic Nkx domain (11). Gtx
is related to Nkx6.1 not only in its sequence but also in
its expression pattern in the developing mouse and chicken neural tube
(4). At the early stage of neural development, both
Nkx6.1 and Nkx6.2 are induced in the ventral
neural tube by the sonic hedgehog midline signaling molecule secreted
from the notochord and floor plate (4, 11). In the
midbrain and hindbrain regions, Nkx6.1 and -6.2
are expressed in similar domains of the ventrolateral neuroepithelium
flanking the floor plate. From the Nkx6.2+
Nkx6.1+ ventral neuroepithelium arise the
cranial motor neurons and serotonergic neurons in the hindbrain
(3, 7) and dopaminergic neurons in the midbrain
(6). Thus, Nkx6.2 transcription factor may play
an important role in the control of neuronal specification and differentiation.
To investigate the function of Nkx6.2 in the specification
and differentiation of neuronal cells, oligodendrocytes, and testis germ cells, we inactivated the mouse Nkx6.2 homeobox gene by
the standard gene targeting approach. The mutant mice were born and grew normally like their littermates. The lack of detectable phenotypes in the development of tissues that express Nkx6.2 suggests a
possible functional compensation from other related homeobox genes,
such as Nkx6.1.
| |
MATERIALS AND METHODS |
Gene targeting.
Genomic DNA including the Nkx6.2
gene was isolated by screening a mouse 129Sv genomic library using the
full-length Nkx6.2 cDNA as a probe. The genomic organization
was determined by restrictive digestions and extensive sequencing. The
replacement targeting vector was constructed by replacing the entire
coding region with a neomycin resistance gene. Targeting vector was
subsequently linearized and introduced into embryonic stem (ES) cells
by electroporation. Genomic DNA isolated from ES clones was digested
with ClaI and SpeI prior to hybridization with
the flanking sequence probe 1, as indicated in Fig.
1A. The wild-type allele gave a band of
10 kb, whereas the targeted allele produced a band of 6.0 kb. Mutant ES
clones were characterized and injected into C57BL blastocysts using the
methods described previously (10).
View larger version (28K):
[in this window]
[in a new window]
|
FIG. 1.
Gene targeting of Nkx6.2. (A) Genomic
organization of the Nkx6.2 locus and the structure of the
targeting vector. Abbreviations for restriction sites: B,
BamHI; C, ClaI; E, EcoRI; Sp,
SpeI; X, XhoI. (B) Southern blot analysis of
BamHI-digested genomic DNA from representative F2 pups with
probe 2. A weak nonspecific band was also seen below the wild-type
allele. (C) PCR genotyping of representative pups using two sets of
primers simultaneously. The UP1 and DP1 primers amplified a 657-bp
fragment from the wild-type allele, whereas the UP2 and DP2 primers
amplified a 760-bp band from the mutant allele. MW, molecular weight
(numbers on the left are base pairs).
|
|
Genotyping the Nkx6.2 mutants.
Southern analysis
and/or PCR was used to genotype the offspring. For Southern analysis,
the genomic DNA was digested with BamHI and hybridized with
probe 2 indicated in Fig. 1A. The wild-type allele was detected as a
5.4-kb band, whereas the mutant was seen as a 4.2-kb band (Fig. 1B).
For genotyping by PCR, two sets of PCR primers were used simultaneously
in the same reaction mixture containing 3% dimethyl
sulfoxide. Primers
UP1 (CTG AAG CTT GAC GCT AAC CGC CCG GGT GCG)
and DP1
(CAC TTG GCT CTC GGT CAT) amplify part of the first exon
(657 bp) in the wild-type allele (Fig.
1A). Primers UP2 (GGA TGT
CTG CAG CCC TGC TTA) and DP2 (TAC CCG TGA TAT TGC TGA AGA
GC)
amplified a 0.76-kb fragment from
Neo to the 3'
flanking sequence
in the mutant allele (Fig.
1A). The PCR conditions
are 95°C for
5 min and 35 cycles of 94°C for 40 s, 60°C for
50 s, and 72°C
for 1
min.
In situ RNA hybridization.
Embryos from various stages of
mouse development were fixed in 4% paraformaldehyde at 4°C
overnight. Tissue preparation and in situ hybridization with
digoxigenin- or fluorescein-labeled riboprobes were performed according
to Schaeren-Wiemers and Gerfin-Moser (13) with minor modifications.
Immunohistochemistry.
Spinal cord and brain tissues were
isolated from various stage of mouse embryos, fixed in 4%
paraformaldehyde, cryosectioned, and immunostained with anti-Islet-1
(Developmental Studies Hybridoma Bank, Iowa City, Iowa) monoclonal
supernatant or anti-tyrosine hydroxylase (TH) (Chemicon) or
antiserotonin (anti-5-HT; DiaSorin) polyclonal antibodies.
Immunohistochemistry was performed with the Vecstain ABC staining kit
(Vector) with diaminobendidine substrate according to the
manufacturer's protocol.
| |
RESULTS |
Targeted disruption of mouse Nkx6.2 gene.
To
determine the role of Nkx6.2 in mouse development, we
inactivated Nkx6.2 by gene targeting. The targeting vector
was designed to replace the entire coding region with the neomycin
gene. Following electroporation and drug selection, 100 independent ES
clones were analyzed by genomic Southern blot with the flanking probe. Eight clones harboring homologous recombination were obtained. Two
mutant ES clones with correct karyotypes were injected into blastocysts
from C57BL mice, and both clones transmitted the mutant allele through
the germ line. Homozygous mice derived from these two lines showed the
same phenotype.
The deletion of
Nkx6.2 was confirmed by the lack of
amplification of the
Nkx6.2 sequence from genomic DNA (Fig.
1C) or from
the reverse-transcribed cDNA from the homozygous mutants
(data
not shown). The
Nkx6.2 mutation was further verified
by in situ
RNA hybridization on midbrain from embryonic day 14.5 (E14.5)
(Fig.
2). As reported previously
(
4),
Nkx6.2 expression is
detected mainly in
the ventral region of the midbrain (Fig.
2A)
and the hindbrain
(
4) in the wild-type embryos.
Nkx6.1 is
expressed
at similar D-V positions (Fig
2B and D) in these regions. In
the
Nkx6.2 homozygous mutants, expression of
Nkx6.2 was not detected
(Fig.
2C), although
Nkx6.1 expression was not compromised in the
midbrain
(Fig.
2D).
View larger version (127K):
[in this window]
[in a new window]
|
FIG. 2.
Lack of Nkx6.2 transcript in the homozygous
mutants. Midbrain sections from E14.5 wild-type (A and B) and
Nkx6.2 mutant (C and D) embryos were used for in situ RNA
hybridization with Nkx6.2 and Nkx6.1 riboprobes.
Nkx6.2 and Nkx6.1 are both expressed in the
ventral midbrain. Expression of Nkx6.2, but not
Nkx6.1, is absent in the mutants.
|
|
Nkx6.2 null mutants have normal growth and reproductive
function.
To determine the effects of Nkx6.2 mutation
on mouse development, heterozygous mice were crossed to obtain
homozygous mutant mice. Genotype analysis of the offspring from the
heterozygous matings showed Mendelian segregation ratios (27:64:34),
indicating that the Nkx6.2 mutation is not lethal.
Homozygous mice were morphologically indistinguishable from their
heterozygous and wild-type littermates and can reproduce normally, with
a typical litter size of 8 to 12 pups.
Nkx6.2 mutation does not affect neuronal
differentiation in the ventral central nervous system.
During the
early stage of neural development, Nkx6.2 is selectively
expressed in the ventral midbrain and hindbrain in close proximity to
the floor plate (4, 11). The ventral neuroepithelial cells
flanking the floor plate give rise to dopaminergic neurons in the
midbrain (6, 7) and serotonergic neurons and cranial motor
neurons in the hindbrain (3, 5, 18). To examine the
dopaminergic neuron phenotype, we stained E12.5 to E18.5 midbrain sections with anti-TH antibody. No apparent differences in staining pattern or staining intensities between wild-type and mutant embryos were observed (Fig. 3). Development of
serotonergic neurons in the E12.5 ventral hindbrain was examined with
anti-5-HT antibody (6). The 5-HT-immunoreactive neurons
were observed adjacent to the ventral midline or floor plate (Fig. 4A
and B) in both wild-type and mutant
embryos. For motor neuron development, we performed in situ RNA
hybridization with HB-9, a motor neuron-specific gene (16)
(Fig. 4C and D), and immunostaining with anti-Islet-1 antibody which
labels motor neuron population (Fig. 4E and F) on E10.5 caudal
hindbrain sections. Both studies revealed no significant difference in
the production and distribution of motor neurons in the wild-type and
mutant embryos.
View larger version (68K):
[in this window]
[in a new window]
|
FIG. 3.
Normal differentiation of dopaminergic neurons in the
ventral midbrain. Cross sections of the midbrain tissues from wild-type
(A, C, and E) and mutant (B, D, and F) animals were immunostained with
anti-TH antibody. Similar numbers and patterns of dopaminergic neurons
are observed in the wild-type and mutants.
|
|
View larger version (94K):
[in this window]
[in a new window]
|
FIG. 4.
Normal differentiation of serotonergic neurons and motor
neurons in the ventral hindbrain in the Nkx6.2 mutants. (A
and B) Detection of serontonergic neurons by immunostaining with
anti-5-HT on horizontal sections of the rostral hindbrain from E12.5
wild-type (A) and mutant (B) embryos. The midline is indicated by the
arrow. (C to F) Detection of cranial motor neurons on cross sections of
the caudal hindbrain from E10.5 wild-type (C and E) and mutant (D and
F) embryos by immunostaining with anti-Islet-1 (C and D) or in situ
hybridization with HB-9 (E and F).
|
|
Nkx6.2 mutation has no apparent effects on
oligodendrocyte development.
Previous studies had demonstrated
that Nkx6.2 is expressed in both the spinal cord and the
brain (1, 8) and in isolated brain oligodendrocytes
(1). The expression of Nkx6.2 (Gtx) parallels that of myelin basic protein (MBP) and proteolipid protein (PLP), suggesting that Nkx6.2 may regulate the expression of
myelin-specific genes during oligodendrocyte differentiation (1,
2). To investigate the role of Nkx6.2 in
oligodendrocyte differentiation, we examined the expression of MBP and
PLP genes in the mutant spinal cord and brain tissues at various
developmental stages by in situ RNA hybridization. MBP expression can
be detected as early as E18.5 (Fig. 5A and
B) and persists in adults (Fig. 5C and
D). Comparison of MBP expression in the wild-type and mutant littermates did not reveal significant differences in the onset and
intensities of MBP expression. The normal expression of MBP was further
confirmed by immunohistochemical staining with anti-MBP polyclonal
antibody (data not shown). Another myelin-specific gene, the PLP gene,
is also similarly expressed in the wild-type and mutant spinal cords
(Fig. 5E and F).
View larger version (72K):
[in this window]
[in a new window]
|
FIG. 5.
Expression of myelin genes in the spinal cord is not
compromised in the Nkx6.2 mutants. Spinal cord sections from
wild-type (A, C, and E) and mutant (B, D, and F) animals were subjected
to in situ hybridization with MBP and PLP genes.
|
|
To examine oligodendrocyte differentiation in the brain tissues, we
examined MBP expression in the white matter of the adult
cortex and
cerebellum, where oligodendrocytes are highly enriched.
In the coronal
sections of the forebrain regions, MBP expression
can be observed in
the corpus callosum of both wild-type and mutant
animals (Fig.
6A and
B). In the cerebellum region, MBP
expression
is detected mainly in the white matter tissues (Fig.
6C and
D)
and appears to be unaffected by the
Nkx6.2 mutation.
View larger version (91K):
[in this window]
[in a new window]
|
FIG. 6.
Normal expression of myelin genes in the
Nkx6.2 mutant brain. Cross sections from adult forebrain (A
and B) and cerebellum and brain stem (C and D) were subjected to in
situ hybridization with an MBP riboprobe. Similar MBP expression was
observed in the corpus callosum (arrows in panels A and B) and
cerebellum white matter (arrowheads in panels C and D) in the wild type
and mutants.
|
|
| |
DISCUSSION |
This study reports that mice harboring a null mutation in the
Nkx6.2 homeobox gene did not display any apparent
developmental and reproductive defects. To date, we have observed
Nkx6.2 mutant mice for more than 1.5 years and did not
detect any obvious phenotypes, including those related to body movement
and life span.
The lack of phenotypes in the development of the ventral midbrain and
hindbrain may reflect functional compensation from related members of
the Nkx family, such as Nkx6.1. Previous studies
demonstrated that Nkx6.1 and Nkx6.2 are expressed
in similar and overlapping regions in ventrolateral domains flanking
the floor plate (4) (Fig. 2). In addition, several other
distantly related Nkx homeobox genes, e.g., Nkx2.2,
Nkx2.9, Nkx5.1, and Nkx5.2, are also expressed in the
ventral neural tube, including the midbrain and hindbrain at a similar
time window (9, 12, 14). These Nkx homeobox genes may have redundant functions in the control of regional patterning and differentiation of the developing central nervous system. Thus, it would be interesting to examine the effects of compound mutations of these Nkx homeobox genes in the future.
It had been demonstrated that expression of Nkx6.2 in
oligodendrocytes was regulated in parallel with MBP and PLP mRNAs
(1). Promoters from both MBP and PLP genes contain
multiple Nkx6.2 (Gtx) binding sites (1,
2). Based on these observations, Nkx6.2 was suggested
to be involved in the regulation of myelin-specific gene expression.
However, the normal expression of MBP and PLP mRNAs in the
Nkx6.2 mutants indicates that Nkx6.2 is not
required for expression of these two major myelin proteins. Again the
lack of oligodendrocyte phenotype in the mutants may be due to a
functional redundancy from other members of the Nkx family,
such as Nkx2.2, which is selectively expressed in
oligodendrocyte progenitor cells (17).
It was also reported that Nkx6.2 (Gtx) was
specifically expressed in germ cells of the testis and thus may
regulates spermatogenesis (8). Interestingly, the testes
of the mutant males are histologically normal (data not shown) and the
homozygous mutants have normal reproductive function, suggesting that
Nkx6.2 may have a redundant function in the development of
testis germ cells.
| |
ACKNOWLEDGMENTS |
We thank Seigo Izumo for the full-length
Nkx6.2 (Gtx) cDNA probe.
This work was supported by NSF (IBN 9808126), NIH (R01 NS37717), and
National Multiple Sclerosis Society.
J.C. and Y.Q. contributed equally to this work.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Anatomical Sciences and Neurobiology, School of Medicine, University of
Louisville, Louisville, KY 40292. Phone: (502) 852-7502. Fax: (502)
852-6228. E-mail: m0qiu001{at}louisville.edu.
| |
REFERENCES |
| 1.
|
Awatramani, R.,
S. Scherer,
J. Grinspan,
E. Collarini,
R. Skoff,
D. O'Hagan,
J. Garbern, and J. Kamholz.
1997.
Evidence that the homeodomain protein Gtx is involved in the regulation of oligodendrocytes myelination.
J. Neurosci.
17:6657-6668[Abstract/Free Full Text].
|
| 2.
|
Awatramani, R.,
J. Beesley,
H. Yang,
H. Jiang,
F. Cambi,
J. Grinspan,
J. Garbern, and J. Kamholz.
2000.
Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity.
J. Neurosci. Res.
61:376-387[CrossRef][Medline].
|
| 3.
|
Briscoe, J.,
L. Sussel,
P. Serup,
D. Hartigan-O'Conner,
T. M. Jessell,
J. L. Rubenstein, and J. Ericson.
1999.
Homeobox gene Nkx-2.2 and specification of neuronal identity by graded sonic hedgehog signaling.
Nature
398:622-627[CrossRef][Medline].
|
| 4.
|
Cai, J.,
T. St Amand,
H. Yin,
H. Guo,
G. Li,
Y. Zhang,
Y. Chen, and M. Qiu.
1999.
Expression and regulation of the chicken Nkx6.2 homeobox gene suggest its possible involvement in the ventral neural patterning and cell fate specification.
Dev. Dyn.
216:459-468.
|
| 5.
|
Ericson, J.,
P. Rashbass,
A. Schedl,
S. Brenner-Morton,
A. Kawakami,
V. van Heyningen,
T. Jessell, and J. Briscoe.
1997.
Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.
Cell
90:169-180[CrossRef][Medline].
|
| 6.
|
Hynes, M.,
K. Poulsen,
M. Tessier-Lavigne, and A. Rosenthal.
1995.
Control of neuronal diversity by the floor plate: contact-mediated induction of midbrain dopaminergic neurons.
Cell
80:95-101[CrossRef][Medline].
|
| 7.
|
Hynes, M., and A. Rosenthal.
1999.
Specification of dopaminergic and serotonergic neurons in the vertebrate CNS.
Curr. Opin. Neurobiol.
9:26-36[CrossRef][Medline].
|
| 8.
|
Komuro, I.,
M. Schalling,
L. Jahn,
R. Bodmer,
N. Jenkins,
N. Copeland, and S. Izumo.
1993.
Gtx: a novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells of testis, has a transcriptional repressor activity in vitro for a serum-inducible promoter.
EMBO J.
12:1387-1401[Medline].
|
| 9.
|
Pabst, O.,
H. Herbrand, and H.-H. Arnold.
1998.
Nkx-2.9 is a novel homeobox transcription factor which demarcates ventral domains in the developing mouse CNS.
Mech. Dev.
73:85-93[CrossRef][Medline].
|
| 10.
|
Qiu, M.,
A. Bulfone,
S. Martinez,
J. Meneses,
K. Shimamura,
R. Pedersen, and J. Rubenstein.
1995.
Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain.
Genes Dev.
9:2523-2538[Abstract/Free Full Text].
|
| 11.
|
Qiu, M.,
K. Shimamura,
L. Sussel,
S. Chen, and J. L. Rubenstein.
1998.
Control of anteroposterior and dorsoventral domains of Nkx-6.1 gene expression relative to other Nkx genes during vertebrate CNS development.
Mech. Dev.
72:77-88[CrossRef][Medline].
|
| 12.
|
Rinkwitz-Brandt, S.,
M. Justus,
I. Oldenettel,
H. H. Arnold, and E. Bober.
1995.
Distinct temporal expression of mouse Nkx-5.1 and Nkx-5.2 homeobox genes during brain and ear development.
Mech. Dev.
52:371-381[CrossRef][Medline].
|
| 13.
|
Schaeren-Wiemers, N., and A. Gerfin-Moser.
1993.
A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labeled cRNA probes.
Histochemistry
100:431-440[CrossRef][Medline].
|
| 14.
|
Shimamura, K.,
D. J. Hartigan,
S. Martinez,
L. Puelles, and J. Rubenstein.
1995.
Longitudinal organization of the anterior neural plate and neural tube.
Development
121:3923-3933[Abstract].
|
| 15.
|
Sim, F.,
G. Hinks, and R. J. Franklin.
2000.
The re-expression of the homeodomain transcription factor gtx during remyelination of experimentally induced demyelinating lesions in young and old rat brain.
Neuroscience
100:131-139[CrossRef][Medline].
|
| 16.
|
Tanabe, Y.,
C. William, and T. Jessell.
1998.
Specification of motor neuron identity by the MNR2 homeodomain protein.
Cell
95:67-80[CrossRef][Medline].
|
| 17.
|
Xu, X.,
J. Cai,
F. Hui,
Y. Qi,
G. Modderman,
R. Liu, and M. Qiu.
2000.
Selective expression of Nkx-2.2 transcription factor in the migratory chicken oligodendrocyte progenitor cells and implications for the embryonic origin of oligodendrocytes.
Mol. Cell. Neurosci.
16:740-753[CrossRef][Medline].
|
| 18.
|
Ye, W.,
K. Shimamura,
J. Rubenstein,
M. Hynes, and A. Rosenthal.
1998.
FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate.
Cell
93:755-766[CrossRef][Medline].
|
Molecular and Cellular Biology, July 2001, p. 4399-4403, Vol. 21, No. 13
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.13.4399-4403.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Prakash, N., Puelles, E., Freude, K., Trumbach, D., Omodei, D., Di Salvio, M., Sussel, L., Ericson, J., Sander, M., Simeone, A., Wurst, W.
(2009). Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain. Development
136: 2545-2555
[Abstract]
[Full Text]
-
Sousa, V. H., Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., Fishell, G.
(2009). Characterization of Nkx6-2-Derived Neocortical Interneuron Lineages. Cereb Cortex
19: i1-i10
[Abstract]
[Full Text]
-
Jin, T.
(2008). Mechanisms underlying proglucagon gene expression. J Endocrinol
198: 17-28
[Abstract]
[Full Text]
-
Klinck, R., Serup, P., Madsen, O. D., Jorgensen, M. C.
(2008). Specificity of Four Monoclonal Anti-Nkx6-1 Antibodies. J. Histochem. Cytochem.
56: 415-424
[Abstract]
[Full Text]
-
Nelson, S. B., Janiesch, C., Sander, M.
(2005). Expression of Nkx6 Genes in the Hindbrain and Gut of the Developing Mouse. J. Histochem. Cytochem.
53: 787-790
[Abstract]
[Full Text]
-
Southwood, C., He, C., Garbern, J., Kamholz, J., Arroyo, E., Gow, A.
(2004). CNS Myelin Paranodes Require Nkx6-2 Homeoprotein Transcriptional Activity for Normal Structure. J. Neurosci.
24: 11215-11225
[Abstract]
[Full Text]
-
Broihier, H. T., Kuzin, A., Zhu, Y., Odenwald, W., Skeath, J. B.
(2004). Drosophila homeodomain protein Nkx6 coordinates motoneuron subtype identity and axonogenesis. Development
131: 5233-5242
[Abstract]
[Full Text]
-
Takahashi, T., Tanaka, H., Iguchi, N., Kitamura, K., Chen, Y., Maekawa, M., Nishimura, H., Ohta, H., Miyagawa, Y., Matsumiya, K., Okuyama, A., Nishimune, Y.
(2004). Rosbin: A Novel Homeobox-Like Protein Gene Expressed Exclusively in Round Spermatids. Biol. Reprod.
70: 1485-1492
[Abstract]
[Full Text]
-
Hashimoto, Y., Tsuji, O., Kanekura, K., Aiso, S., Niikura, T., Matsuoka, M., Nishimoto, I.
(2004). The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain. J. Biol. Chem.
279: 16767-16777
[Abstract]
[Full Text]
-
Jeong, Y., Epstein, D. J.
(2003). Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Development
130: 3891-3902
[Abstract]
[Full Text]
Top
Abstract
Introduction
