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(Received for publication, September 10, 1996, and in revised form, October 17, 1996)
From the ¶ Department of Virology, Jerome H. Holland
Laboratory, Rockville, Maryland 20855, the ABSTRACT A new member of the mouse NK family of homeobox
genes that is related to Drosophila NK-3 has been
identified. Expression of this gene, termed Nkx-3.1, is
largely restricted to the prostate gland in adult animals. The level of
Nkx-3.1 mRNA decreases markedly in response to
castration, suggesting that its expression is
androgen-dependent. In situ hybridization
analyses demonstrated that expression of Nkx-3.1 in the
prostate is confined to epithelial cells. In newborns, Nkx-3.1 mRNA is detected in the urethral epithelium
that is being induced by the surrounding mesenchyme to invaginate to
form prostatic buds. Together, these observations suggest that the
Nkx-3.1 protein, which likely functions as a transcription
factor, plays a prominent role both in the initiation of prostate
development and in the maintenance of the differentiated state of
prostatic epithelial cells.
INTRODUCTION The discovery of the homeobox as a conserved DNA sequence
element in several Drosophila genes responsible for
controlling the identity of body segments prompted searches for related
genes in other organisms. Homeoboxes have since been discovered in the genome of all metazoan organisms, and several hundred unique homeobox genes have been defined in mice and humans (1, 2). The homeobox encodes
a 61-amino acid domain, termed the homeodomain, that includes a
helix-turn-helix motif that is structurally related to the DNA-binding domain of several procaryotic proteins and to the products of the yeast
mating type locus (3, 4). NMR and crystallographic analyses have
confirmed that the homeodomain binds DNA (5, 6). Both biochemical and
genetic analyses have established that the products of homeobox genes
are transcriptional regulatory molecules (7).
The predicted amino acid sequence of the known homeodomains serves as
the principal identifier that allows them to be classified into a
minimum of 20 distinct groups (1, 2). The NK family of homeobox genes,
first defined by four Drosophila genes, NK-1 through NK-4, can be separated into two classes.
NK-2, -3, and -4 are more related to
each other than to other homeobox genes, whereas NK-1 is a
more distant relative (8). In mouse, six NK-2-like genes
have been identified (9, 10). Three of these are more related to
NK-2 than the others, and may themselves form a distinct
subclass (10). To date, no mouse genes closely related to
NK-3 or NK-4 have been characterized.
Many studies aimed at characterizing functions of homeobox genes have
focused principally on developmental roles (7, 11). A prominent example
is the Hox family of genes, whose members have been demonstrated to
play critical roles in pattern formation during embryogenesis along the
anteroposterior body axis of divergent species (11). Some Hox genes and
members of other classes of homeobox genes are also expressed during
organogenesis, and a few have been reported to be expressed in adult
tissues. Surprisingly, the potential roles of homeobox genes in
differentiated tissues and organs have received comparatively little
attention. However, the need for patterning functions to maintain the
differentiated states of cell populations and to direct the renewal of
specific cell types in adults is axiomatic.
Our interest in prostate gland development prompted us to search for
homeobox genes whose expression in adults was limited to this tissue.
We have identified a new member of the NK class of genes that fulfills
this criterion. Here, we report the cloning of a mouse homolog of the
Drosophila NK-3 gene, characterize its expression in adult
and newborn tissues, and demonstrate that its expression is
androgen-dependent.
EXPERIMENTAL PROCEDURES Recombinant DNA techniques were performed essentially as
described (12). For Northern blot analyses, 10 µg of RNA prepared as
described (13) was separated on a 0.8% denaturing gel, transferred to
nitrocellulose, and hybridized to a probe consisting of
1.6-kb1 PstI restriction
fragment containing exon 2 and 3 RESULTS AND DISCUSSION A new mouse gene, Nkx-3.1, was isolated from a genomic
library by hybridization with a human probe containing a homeobox
sequence first identified in an expressed sequence tag from a prostate carcinoma cDNA library. Southern blot analysis of human genomic DNA
using a 1.6-kb fragment of the human gene under high stringency revealed a single hybridizing component after digestion with a panel of
restriction endonucleases, indicating that the probe recognized a
single copy gene. Low stringency hybridization of mouse genomic DNA
using the human probe also showed a single hybridizing component with
most restriction enzymes (data not shown). Using the human probe to
screen a mouse genomic PstI library, a single strongly
hybridizing colony was identified. Sequence analysis of the mouse clone
revealed the presence of an open reading frame encoding a homeodomain
that was 100% identical to the human homeodomain. Southern blot
analysis of mouse genomic DNA using a homeodomain-containing probe
derived from the cloned mouse gene revealed a pattern of hybridization
that was identical to the pattern observed using the human probe under
low stringency, demonstrating that the mouse and human genes are
equivalent.
Sequence of the homeodomain showed highest homology to the NK class of
genes (52-77%). A tyrosine residue at position 54 within helix 3 provided further evidence that this homeodomain belongs to the NK
family, since it is a common feature of Drosophila NK-2, -3, and -4, as well as all of their known
vertebrate homologs (1, 2, 10). The highest degree of homology was to
the Drosophila NK-3 homeodomain, with identity at 47 of 61 positions (77%). In contrast, identity with NK-2 and
NK-4 was 60 and 52%, respectively. Hence, we named this
gene Nkx-3.1. Although clearly related, it should be noted
that mouse Nkx-3.1 may not represent a true homolog of
Drosophila NK-3. This suggestion is supported by the fact
that among mouse NK-2-like genes, identity with
Drosophila NK-2 ranges from 68 to as high as 95% (10). In
addition, low stringency Southern blot hybridization analysis using an
Nkx-3.1 homeodomain-containing probe showed several
cross-hybridizing components, suggestive of the presence of multiple
Nkx-3.1-like genes (data not shown).
Analysis of residues conserved between NK-3 and
Nkx-3.1 revealed a pattern of four amino acids that never
occur together in any other known homeodomain: alanine 6, histidine 10, lysine 36, and lysine 59 (Fig. 1). No other homeodomain
contains three of the four together, and only one contains two of the
four. Hence, these NK-3-defining positions are distinct from
those that distinguish NK-1- and NK-2-related
genes and are also not found in NK-4. We propose that these
positions will define the NK-3-related subclass of NK
genes.
The genomic organization of Nkx-3.1 has been determined by
DNA sequence analysis of genomic and cDNA clones. Typical of
most vertebrate homeobox genes, the coding region is divided into two exons with the homeodomain lying within exon 2. Exon 1 encodes 96 amino
acids, with no discernible functional peptide motifs. Exon 2 encodes
the homeodomain, as well as 28 N-terminal and 53 C-terminal amino
acids. The predicted transcriptional start site, determined by sequence
analysis of 5 The distribution of Nkx-3.1 mRNA was assessed by
Northern blot analysis of RNA isolated from adult tissues (Fig.
2A). Hybridization of a 1.6-kb probe from the
3
The mouse prostate is comprised of four paired components that are
heterogeneous both in morphology and function (19). To further
characterize expression of Nkx-3.1 within the prostate, the
ventral prostate, the dorsolateral prostate, and the coagulating gland
(anterior prostate) were dissected from adult mice. The dorsolateral
prostate was further subdivided into its dorsal and lateral components
(14). To determine if Nkx-3.1 mRNA was differentially distributed among the four lobes, Northern blot analysis was performed on RNA extracted from pools of individual lobes (Fig. 2B).
All four lobes expressed Nkx-3.1 at a similar steady-state
level relative to The maintenance of differentiated functions within the prostate is well
established to be androgen-dependent (20).
Castration-induced androgen deprivation leads to a rapid shut-off of
genes encoding prostate-specific secretory proteins (21). To determine
whether Nkx-3.1 was regulated in response to orchidectomy,
RNA was extracted from prostates harvested at various time points after
castration, but prior to the onset of an atrophic state. Northern blot
analysis revealed that by 24 h after castration, the steady-state
level of Nkx-3.1 mRNA was decreased nearly 10-fold (Fig.
3). By 96 h, the level was decreased 30-fold. These
data suggest that the maintenance of a high level of expression of
Nkx-3.1 requires testicular androgens. It is important to
note that the response of Nkx-3.1 to castration could be
indirect, especially in light of the well established importance of
mesenchymal androgen receptor expression in prostate development (22).
However, several recent studies have clearly demonstrated androgen
receptor expression in prostate epithelial cells soon after the
emergence of prostatic buds and its maintenance in both luminal and
basal epithelial cells (23, 24). These observations leave open the
possibility that the response of Nkx-3.1 may be direct.
The same RNA blot was subsequently hybridized with a probe that
detected the mRNA encoding a secreted protease inhibitor, mp12, that has been demonstrated to be
androgen-dependent (21). A comparison of the kinetics and
extent of down-regulation showed that the level of mp12
mRNA was decreased by more than 70-fold by 24 h after
castration. At 96 h, mp12 mRNA was no longer
detectable by Northern analysis, whereas Nkx-3.1 mRNA
fell to a basal level that was maintained for at least several more
days. These data suggest that Nkx-3.1 expression is
androgen-responsive, but also show a low, basal level of expression
that may not be androgen-dependent.
To characterize the cellular distribution of Nkx-3.1 within
the prostate gland, in situ hybridization to histological
sections was performed. The architecture of the adult prostate is
relatively simple, consisting principally of a series of branching
ducts lined with secretory epithelial cells (14). The ducts are wrapped by condensed stromal sleeves with sparse connective tissue interspersed between the ducts. Analysis of serial sections hybridized with antisense and control sense probes showed signal only with the antisense probe, confirming the specificity of hybridization
(cf. Figs. 4, A and B).
Within sections of each lobe, hybridization signal was detected
exclusively over the epithelial cells lining the ducts (Figs. 4,
C-F). Stromal cells did not show detectable expression of
Nkx-3.1. Consistent with the results of the Northern blot
analyses, there was no distinguishable difference in the intensity of
the signal over epithelial cells from individual lobes. These
observations demonstrate that Nkx-3.1 mRNA is confined to epithelial cells in the adult prostate and are consistent with a
role for this gene in the maintenance of differentiated prostate functions.
Our observation of restricted, androgen-dependent
expression of Nkx-3.1 in adult prostate prompted us to
determine whether this gene may be involved in prostate development. In
mice, development of the prostate initiates several days before birth
(14) when the urethral epithelium begins to invade a condensation of
mesenchymal cells near the neck of the bladder. Hybridization of serial
transverse sections of newborn mice demonstrated that
Nkx-3.1 mRNA is expressed in the budding urethral
epithelium as it invaginates into the mesenchyme (Figs. 5,
A and B). No hybridization signal
was detected over mesenchymal cells nor over urethral epithelial cells
in the same region that did not invaginate to form prostatic buds
(Figs. 5, A-D). The strongest hybridization signal was
observed over epithelial cells that had deeply invaded the mesenchyme
(Figs. 5, C and D). Buds from ventral and
dorsolateral lobes and the coagulating gland all expressed
Nkx-3.1 mRNA, consistent with results of Northern blot
analysis of adult prostates. These observations strongly implicate
Nkx-3.1 in the differentiation of the urethral epithelium
into the highly specialized prostate epithelium. Given that the
Nkx-3.1 protein is likely to function as a transcription factor and its expression is restricted to the prostate anlage, it
seems likely that the Nkx-3.1 gene is playing a primary role in driving the differentiation of the prostate gland.
The identification of a new gene encoding a putative transcription
factor that is restricted to the prostate represents a significant
advance in our understanding of prostate physiology and development.
Our observations strongly suggest that Nkx-3.1 plays a role
in both the differentiation of the urethral epithelium into prostatic
epithelium in response to signals arising from the surrounding
mesenchyme. The continued expression of this gene in all four component
lobes in adult animals suggests that it may further be involved in the
maintenance of this tissue. Elucidation of target genes regulated by
this putative transcription factor may provide further insights into
the molecular basis of prostatic differentiation and growth.
FOOTNOTES The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) U73460[GenBank]. REFERENCES
Volume 271, Number 50,
Issue of December 13, 1996
pp. 31779-31782
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
,
Department of
Biochemistry and Molecular Biology, George Washington University
Medical Center, Washington, D. C. 20037, and " Human Genome
Sciences, Inc., Rockville, Maryland 20850
-noncoding sequences. Microdissection
of prostate glands into component lobes was performed as described
(14). Orchidectomy was performed on 6-week-old CD-1 mice as described
for rats (15). RNA was extracted from total prostate, pooled from two
mice, at each time point after castration. Densitometric analysis of
Northern blot autoradiograms was performed using Bioimage Software
version 4.6P (Bioimage Inc., Ann Arbor, MI). For 5 RACE analysis (16),
a reverse transcription primer, 5-GACTCCTTGACATCAGCCAC-3, was used to
generate cDNA from 2 µg of total prostate RNA. PCR was performed
for 30 cycles using a specific nested primer,
5-GCAGTTATCAGCAGAACTGTTG-3, with RACE kit components according to the
manufacturer's recommendations (Boehringer Mannheim). In
situ hybridization was performed essentially as described (17),
using a 530-base synthetic RNA probe derived entirely from the
3-noncoding region.
Fig. 1.
Comparison of the Nkx-3.1
homeodomain sequence with other NK-related homeodomains. Shaded
boxes indicate positions that are conserved between members of a
subclass. Alanine 6, histidine 10, lysine 36, and lysine 59 may define
the NK-3 subclass of vertebrate homeodomains.
[View Larger Version of this Image (28K GIF file)]
RACE clones, lies 24 bases upstream of the initiation
codon. Consistent with the 5 RACE analysis, a TATA box was identified
24 bases 5 of the predicted RNA start site, and two CAAT boxes were
found to lie 32 and 61 bases upstream of the TATA box. Comparison of
the organization of the transcript deduced by sequence analysis to the
length of the mRNA observed in Northern blot analyses predicted a
3-untranslated region of approximately 2500 bases.
-noncoding region under high stringency conditions identified a
3.2-kb transcript exclusively in the prostate. The Nkx-3.1
transcript was not detected by Northern analysis in brain, ovary,
uterus, testis, liver, or heart (Fig. 2A). It was also not
found in epididymis, seminal vesicle, spinal cord, thymus, intestine,
stomach, salivary gland, muscle, lung, spleen, and kidney by Northern
blot analysis (data not shown). An RT-PCR assay was further used to
determine whether a low level of Nkx-3.1 mRNA could be
detected in certain tissues. Low levels of accumulation, estimated to
be less than one one-hundredth that observed in prostate were detected
in testis, seminal vesicle, adrenal gland, salivary gland, brain, and
thymus (data not shown). Notably, no signal was observed in RNA
isolated from mammary gland, despite the fact that human mammary tumors
may express prostate-specific antigen (18). Of the positive tissues,
testis and seminal vesicle showed the highest steady-state levels of
Nkx-3.1 mRNA. It will be of interest to determine
whether the observed signal is due to substantial expression of
Nkx-3.1 in a small subset of cells, or alternatively, to a
low level of accumulation in many cells. These data demonstrate that
Nkx-3.1 expression is largely restricted to prostate,
suggesting that Nkx-3.1 may play a role in controlling
prostate-restricted gene expression and function.
Fig. 2.
Northern blot analyses of Nkx-3.1
expression in adult tissues. A (top),
hybridization of the Nkx-3.1 probe. Lane 1, heart; lane 2, liver; lane 3, testis; lane
4, brain; lane 5, uterus; lane 6, ovary;
lane 7, prostate gland. A (bottom),
hybridization of the same blot with a 
-actin probe. B
(top), hybridization of the Nkx-3.1 probe to
isolated prostate lobes. Lane 1, coagulating gland;
lane 2, ventral prostate; lane 3, lateral
prostate; lane 4, dorsal prostate; lane 5,
seminal vesicle; lane 6, preputial gland. B
(bottom), hybridization of the same blot with a -actin probe.
[View Larger Version of this Image (73K GIF file)]
-actin, suggesting that Nkx-3.1 may be
important for regulating functions that are shared between them.
Fig. 3.
Effect of castration on Nkx-3.1
expression. Orchidectomy was performed on 6-week-old CD-1 mice. At
each time point after castration, total prostate RNA from two mice was
pooled and analyzed by Northern blot analysis for expression of
Nkx-3.1 and mp12. The level of mRNA at each
time point was determined by densitometric analysis of Northern blot
autoradiograms, using -actin mRNA level in the same samples for
normalization.
[View Larger Version of this Image (14K GIF file)]
Fig. 4.
In situ hybridization analysis of
Nkx-3.1 expression in adult prostate. A,
dark-field photomicrograph of a section of the lateral prostate
hybridized with the Nkx-3.1 antisense probe. Strong
hybridization signal was confined to ductal structures. B,
dark-field view of a section adjacent to that shown in A
hybridized with the control sense probe exposed for the same period and
photographed under identical conditions. The marked difference in
signal between the antisense and sense probes demonstrated the
specificity of the antisense probe. C and D,
bright-field (C) and dark-field (D) high
magnification views of a section of the lateral prostate. Silver grains
indicative of probe hybridization were found exclusively over
epithelial cells. E and F, bright-field
(E) and dark-field (F) views of a section of the
dorsal prostate hybridized with the Nkx-3.1 probe.
Hybridization signal is clearly confined to epithelial cells in this
lobe also. ec, epithelial cells; sc, stromal
cells.
[View Larger Version of this Image (116K GIF file)]
Fig. 5.
In situ hybridization analysis of
Nkx-3.1 expression in newborn prostate. A and
B, dark-field (A) and bright-field (B)
views of a section through the prostatic region of the urethra. Hybridization signal is confined to the epithelial cells that have
invaded the mesenchyme. C and D, dark-field
(C) and bright-field (D) high magnification views
of a single dorsolateral epithelial bud. The strongest hybridization
signal was observed over the deeply invaginated epithelial cells.
dl, dorsolateral buds; vt, ventral buds;
pe, prostatic epithelium; ue, urethral
epithelium.
[View Larger Version of this Image (134K GIF file)]
1
The abbreviations used are: kb, kilobase(s);
RACE, rapid amplification of cDNA ends; RT-PCR, reverse
transcription-polymerase chain reaction.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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M. Treier, A. S. Gleiberman, S. M. O'Connell, D. P. Szeto, J. A. McMahon, A. P. McMahon, and M. G. Rosenfeld Multistep signaling requirements for pituitary organogenesis in vivo Genes & Dev., June 1, 1998; 12(11): 1691 - 1704. [Abstract] [Full Text]
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