Abdominal-B
Abdominal-B homologs and axial and organ patterning The mouse and human Hox complex consists of 39 genes in four linkage groups (A-D). Although the
structure and expression patterns of most of these genes have been reported, the 5' members of the
Hox C linkage group have been only partially characterized. The primary and
genomic structure of the mouse Hoxc11 gene is described as well as its expression pattern. The Hoxc11 gene
encodes a 304 amino acid protein that is translated from a 2.2 kb transcript, derived from two exons.
Hoxc11 mRNA is found in the most posterior region of the developing embryo, commencing at 9.5
days of gestation. Expression is detected in the posterior neural tube, dorsal root ganglia, prevertebrae
and hindlimbs. Expression is also found in metanephric mesenchyme; later in development, this
becomes restricted to the cortical region of the developing kidney. In the developing genitalia,
prominent expression is first observed in the posterior urogenital sinus that gives rise to the urethra,
vagina and prostate. Later, expression is seen in paramesonephric and mesonephric ducts and in the
genital tubercle. In the hindlimbs, Hoxc11 expression is seen in the mesenchyme, posterior to the region
forming the femur and fibula, but does not extend anteriorly to the region giving rise to the tibia or
distally to the tarsal bones. It is thought that Hoxc11 plays a prominent role in the formation of the kidney and reproductive organs (Hostikka, 1998).
Hox A11 mutant mice exhibit
double homeotic transformations, with the thirteenth thoracic segment posteriorized to form an
additional first lumbar vertebra and with the sacral region anteriorized, generating yet another
lumbar segment. Furthermore, skeletal malformations are observed in both forelimbs and
hindlimbs. In mutant forelimbs, the ulna and radius are misshapen, the pisiform and triangular
carpal bones are fused, and abnormal sesamoid bone development occurs. In mutant hindlimbs
the tibia and fibula are joined incorrectly and malformed at their distal ends. Also, an enlarged
sesamoid develops ventral to the tibiale bone. Both heterozygous and homozygous mice display
mutant phenotypes adding an additional level of complexity to the Hox code hypothesis (Small, 1993).
A phylogenetically conserved transcriptional enhancer necessary for the activation of Hoxd-11 was deleted from the HoxD complex of
mice by targeted mutagenesis. While genetic and expression analyses demonstrate the role of this regulatory element in the activation
of Hoxd-11 during early somitogenesis, the function of this gene in developing limbs and the urogenital system is not affected,
suggesting that Hox transcriptional controls are different in different axial structures. In the trunk of mutant embryos, transcriptional
activation of Hoxd-11 and Hoxd-10 is severely delayed, but subsequently resumes with appropriate spatial distributions. The
resulting caudal transposition of the sacrum indicates that proper vertebral specification requires a precise temporal control of Hox
gene expression, in addition to spatial regulation. A slight time delay in expression (transcriptional heterochrony) cannot be
compensated for at a later developmental stage, eventually leading to morphological alterations (Zakany, 1997).
Homologs of homeobox tail genes of the fly are expressed in the head of the mouse.
Different mouse Hox genes expressed in transgenic flies have spatially restricted effects which correlate with their genetic order and expression pattern in the mouse. The generalized expressions of Hoxd-8 and Hoxd-9 modify
Drosophila anterior head segment(s), but have no effect in the rest of the body. Hoxd-10
expression affects head and thorax, but not the abdomen. Hoxd-11 alters abdomen as well as head and thorax. The developmental effect of the Hox genes consists of a homeotic transformation of the affected segment(s), which exhibit a 'ground' pattern similar to that obtained in the absence of homeotic information, suggesting that Hox genes are able to inactivate Drosophila homeotic genes, but do not specify a pattern of their own. A partial exception is Hoxd-11 . Even though it has a general suppressing effect, it can also activate the resident Abdominal-B and empty spiracles genes in ectopic positions. These results strongly suggest a general conservation of the functional hierarchy of homeotic genes that correlates with genetic order and expression patterns (Bachiller, 1994).
Hoxd-12 and Hoxd-13, the two most posterior Hoxd genes are expressed in the terminal part of the hindgut mesoderm, in the presumptive musculosa, which will generate, after birth, the circular and longitudinal layers of muscles. Expression of both genes is strong and overlapping, up to the most distal part, i.e. the level of the internal sphincter that demarcates the anorectal transition. In addition, Hoxd-13 but not Hoxd-12 is heavily expressed in rectal epithelium, which is derived from definitive endoderm, while undetectable in squamous anal epithelium, which derives from the ectoderm. When Hoxd-13 or Hoxd-12 is inactivated, the morphology of the internal sphincter is deeply disorganized. In particular the longitudinal muscle layer is severly reduced or partially absent (Kondo, 1996).
Hoxa-10, an Abd-B class homeodomain protein, is expressed in the uterus during pregnancy. Examination of pregnancy in Hoxa-10 knockouts has revealed failure of implantation as well as resorption of embryos in the early postimplatantion period. In addition there is a homeotic transformation of the proximal 25% of the uterus into ovoduct which is unrelated to the failure of implantation (Benson, 1996).
Using a xenograft model of fetal intestinal anlagen implanted under the
skin of nude mice, the expression of five homeobox genes
(HoxA-4, HoxA-9, HoxC-8, Cdx-1 and Cdx-2) was examined. In homotypic associations of fetal endoderm and mesenchyme that
recapitulate normal development, the overall pattern of homeobox gene expression is
maintained: HoxA-9 (homologous to Drosophila Abd-B) and HoxC-8 (homologous to Drosophila abd-A) were the highest in the colon and ileum, respectively, and
HoxA-4 (homologous to Drosophila Deformed) is expressed all along the intestine. Cdx-1 and Cdx-2 (Both homologs of Drosophila caudal) exhibit an increasing
gradient of expression from small intestine to colon. Grafting per se causes a faint
upregulation of HoxA-9 and HoxC-8 in small intestinal regions where these genes are not
normally expressed, while the endoderm-mesenchyme dissociation-association step
provokes a decay of Cdx-1 in the colon. In heterotopic associations of colonic endoderm
with small intestinal mesenchyme, the colonic epithelium exhibits heterodifferentiation into a
small intestinal-like phenotype. In this case, a decay of HoxA-9 expression and
an upregulation of HoxC-8 is observed. Heterodifferentiation of the colonic epithelium is
accompanied by a downregulation of Cdx-1 and Cdx-2 to a level similar to that found in the
normal small intestine. To demonstrate that mesenchyme-derived cells can influence Cdx-1
and Cdx-2 expression in the bowel epithelium, fetal jejunal endoderm was associated with
intestinal fibroblastic cell lines that either support small intestinal-like or colonic-like
morphogenesis. A lower expression of both homeobox genes occurs in grafts presenting
the small intestinal phenotype than in those showing glandular colonic-like differentiation.
Taken together, these results suggest that homeobox genes participate in the control of the
positional information and/or cell differentiation in the intestinal epithelium. They also
indicate that the level of Cdx-1 and Cdx-2 homeobox gene expression is influenced by
epithelial-mesenchymal cell interactions in the intestinal mucosa (Duluc, 1997).
Gene targeting experiments have shown that the murine Hoxa-13 and Hoxd-13 paralogous genes control skeletal patterning in the distal region of the developing limbs. However, both genes are also
expressed in the terminal part of the digestive and urogenital tracts during embryogenesis and postnatal
development. Abnormalities are described that occur in these systems in Hoxa-13(-/-) and
Hoxa-13/Hoxd-13 compound mutant mice. Hoxa-13(-/-) mutant fetuses show agenesis of the caudal portion of the Mullerian ducts, lack of development of the presumptive urinary bladder and premature
stenosis of the umbilical arteries, which could account for the lethality of this mutation at mid-gestational stages. Due to such lethality, only Hoxa-13(+/-)/Hoxd-13(-/-) compound mutants can reach adulthood. These compound mutants display (1) agenesis or hypoplasia of some of the male accessory sex glands, (2) malpositioning of the vaginal, urethral and anal openings, and improper separation of the vagina from the urogenital sinus, (3) hydronephrosis and (4) anomalies of the muscular and epithelial layers of the rectum. Thus, Hoxa-13 and Hoxd-13 play important roles in the morphogenesis of the terminal part of the gut and urogenital tract. While Hoxa-13(-/-)/Hoxd-13(+/-) fetuses show severely impaired development of the urogenital sinus, double null (Hoxa-13[-/-]/Hoxd-13[-/-]) fetuses display no separation of the terminal (cloacal) hindgut cavity into a urogenital sinus and presumptive rectum, and no development of the genital bud, thereby demonstrating that both genes act, in a partly redundant manner, during early morphogenesis of posterior trunk structures (Warot, 1997).
A number of models attempt to explain the functional relationships of Hox genes. The functional equivalence model states
that mammalian Hox-encoded proteins are largely functionally equivalent, and that Hox quantity is more important than
Hox quality. In this report, the results of two homeobox swaps are described. In one case, the homeobox of Hoxa 11 was
replaced with that of the very closely related Hoxa 10. Developmental function was assayed by analyzing the phenotypes
of all possible allele combinations, including the swapped allele, and null alleles for Hoxa 11 and Hoxd 11. This chimeric
gene provided wild-type function in the development of the axial skeleton and male reproductive tract, but served as a
hypomorph allele in the development of the appendicular skeleton, kidneys, and female reproductive tract. In the other case,
the Hoxa 11 homeobox was replaced with that of the divergent Hoxa 4 gene. This chimeric gene provided near recessive null
function in all tissues except the axial skeleton, which developed normally. These results demonstrate that even the most
conserved regions of Hox genes, the homeoboxes, are not functionally interchangeable in the development of most tissues.
In some cases, developmental function tracked with the homeobox, as previously seen in simpler organisms. Homeoboxes with more 5' cluster positions were generally dominant over more 3' homeoboxes, consistent with phenotypic suppression seen in Drosophila. Surprisingly, however, all Hox homeoboxes tested did appear functionally equivalent in the formation of the axial skeleton. The determination of segment identity is one of the most evolutionarily ancient functions of Hox genes. It is interesting that Hox homeoboxes are interchangeable in this process, but are functionally distinct in other aspects of development (Zhao, 2002).
Initiation of Hox genes requires interactions between numerous factors and
signaling pathways in order to establish their precise domain boundaries in
the developing nervous system. There are distinct differences in the
expression and regulation of members of the Hox gene family within a complex, suggesting
that multiple competing mechanisms are used to initiate Hox gene expression
domains in early embryogenesis. In this study, by analyzing the response of
HoxB genes to both RA and FGF signaling in neural tissue during early
chick embryogenesis (HH stages 7-15), two distinct groups of
Hox genes have been defined based on their reciprocal sensitivity to RA or FGF during this developmental period. The sharp reciprocal transition from RA to FGF responsiveness in moving from the 3' (Hoxb1 to Hoxb5) to the 5' (Hoxb6-Hoxb9) Hox genes is surprising. In mouse the 3' Hox genes do not respond
uniformly to RA treatment, since there is a progressive temporal shift in their competence or ability to respond to RA during gastrulation, such that
successively more 5' genes respond in later time windows. Hence, it had been suggested that the most posterior 5' Hox genes might also be progressively sensitive to RA in later stages at the end of or after gastrulation. The expression domain of 5' members from the HoxB complex (Hoxb6-Hoxb9) can be expanded anteriorly in the chick neural tube up to the level of the otic vesicle following FGF treatment and these same genes are refractory to RA treatment at these stages (Bel-Vialar, 2002).
The chick caudal-related genes, cdxA and cdxB, are also responsive to FGF signaling in neural tissue and their anterior expansion
is also limited to the level of the otic vesicle. Using a dominant negative
form of a Xenopus Cdx gene (XcadEnR) it has been found that the
effect of FGF treatment on 5' HoxB genes is mediated in part
through the activation and function of CDX activity. Conversely, the 3'
HoxB genes (Hoxb1 and Hoxb3-Hoxb5) are sensitive to
RA but not FGF treatments at these stages. In ovo
electroporation of a dominant negative retinoid receptor construct
(dnRAR) shows that retinoid signaling is required to initiate expression.
Elevating CDX activity by ectopic expression of an activated form of a
Xenopus Cdx gene (XcadVP16) in the hindbrain ectopically
activates and anteriorly expands Hoxb4 expression. In a similar
manner, when ectopic expression of XcadVP16 is combined with FGF
treatment, it was found that Hoxb9 expression expands anteriorly into the
hindbrain region. These findings suggest a model whereby, over the window of
early development examined, all HoxB genes are actually competent
to interpret an FGF signal via a CDX-dependent pathway. However, mechanisms
that axially restrict the Cdx domains of expression, serve to prevent
3' genes from responding to FGF signaling in the hindbrain. FGF may have
a dual role in both modulating the accessibility of the HoxB complex
along the axis and in activating the expression of Cdx genes. The
position of the shift in RA or FGF responsiveness of Hox genes may be time
dependent. Hence, the specific Hox genes in each of these complementary groups
may vary in later stages of development or other tissues. These results
highlight the key role of Cdx genes in integrating the input of
multiple signaling pathways, such as FGFs and RA, in controlling initiation of
Hox expression during development and the importance of understanding
regulatory events/mechanisms that modulate Cdx expression (Bel-Vialar, 2002).
It is generally held that vertebrate muscle precursors depend totally on environmental cues for their development. Instead, it is shown that somites are predisposed toward a particular myogenic program. This predisposition depends on the somite's axial identity: when flank somites are transformed into limb-level somites, either by shifting somitic boundaries with FGF8 or by overexpressing posterior Hox genes, they readily activate the program typical for migratory limb muscle precursors. The intrinsic control over myogenic programs can only be overridden by FGF4 signals provided by the apical ectodermal ridge of a developing limb (Alvares, 2003).
Since the competence to start a particular program of hypaxial myogenesis is linked to the position of the somites along the anteroposterior body axis, it was reasoned that this competence may be a consequence of the somite's axial identity. Indeed, when the ability was exploited of FGF8 to move the somitic boundaries, thereby changing the axial identity of somites in the flank into the identity of hindlimb-level somites, these somites gained the ability to produce Lbx1-expressing migratory muscle precursors (MMPs). This suggests that the positional values intrinsic to the somites determine their competence to generate either migratory or nonmigratory hypaxial muscle precursors (Alvares, 2003).
It is established that the axial identity of somites is controlled by the overlapping expression of Hox/HOM genes. In particular, a code of Hox gene expression is conserved for crucial anatomical landmarks such as the neck-thorax transition. Significantly, conserved Hox gene expression boundaries also demarcate the transition of limb-flank somites. Moreover, Hox gene expression patterns are maintained when somites are heterotopically grafted, as is the ability to express the MMP marker Lbx1. It was therefore reasoned that Hox genes may control the somitic competence to initiate a particular myogenic program. To test this possibility, expression constructs were engineered for HoxD9 and HoxA10, both normally present in hindlimb-level somites but not in the flank. Upon electroporation of either of the constructs into flank somites, these somites readily expressed Lbx1, while control constructs were unable to evoke expression of the Lbx1 gene. Thus, Lbx1 expression-directly or indirectly-is under the control of Hox genes (Alvares, 2003).
Anteroposterior (AP) patterning of the developing neural tube is crucial for both regional specification and the timing of neurogenesis. Several important factors are involved in AP patterning, including members of the WNT and FGF growth factor families, retinoic acid receptors, and HOX genes. The interactions between FGF and retinoic signaling pathways have been studied. Blockade of FGF signaling downregulates the expression of members of the RAR signaling pathway, RARalpha, RALDH2 and CYP26. Overexpression of a constitutively active RARalpha2 rescues the effects of FGF blockade on the expression of XCAD3 and
HOXB9. This suggests that RARalpha2 is required as a downstream target of FGF signaling for the posterior expression of XCAD3 and HOXB9. Surprisingly, it was found that posterior expression of FGFR1 and FGFR4 is dependent on the expression of RARalpha2. Anterior expression is also altered with FGFR1 expression being lost, whereas FGFR4 expression is expanded beyond its normal expression domain. RARalpha2 is required for the
expression of XCAD3 and HOXB9, and for the ability of XCAD3 to induce HOXB9 expression. It is concluded that RARalpha2 is required at multiple points in the posteriorization pathway, suggesting that correct AP
neural patterning depends on a series of mutually interactive feedback loops
among FGFs, RARs and HOX genes (Shiotsugu, 2004).
Vertebrate Hox genes are generally believed to initiate
expression at the primitive streak or early neural plate stages. The
timing and spatial restrictions of the Hox expression patterns
during these stages correlate well with their demonstrated role in axial
patterning. One zebrafish hoxc13 ortholog, hoxc13a, has an
expression pattern in the developing tail bud that is consistent with
the gene playing a role in axial patterning. However, the second
hoxc13 ortholog, hoxc13b, is maternally expressed and is
detectable in every cell of early cleavage embryos through gastrulae. In
addition, both transcript and protein are detectable at these stages. At
19 h post fertilization (hpf), hoxc13b expression is up-regulated
in the tail bud, becoming restricted to the tail bud by 24 hpf.
Importantly, by 24 hpf, hoxc13b morphants show a specific
developmental delay, which can be rescued by co-injecting synthetic
capped hoxc13a or hoxc13b message. These data suggest some
functional divergence due to altered expression patterns of the two
hoxc13 orthologs after duplication. Further characterization of
the hoxc13b morphant delay reveals that it is biphasic in nature,
with the first phase of the delay occurring before gastrulation,
suggesting a new role for vertebrate Hox genes before their
conserved role in axial patterning. The extent of the delay does not
change through 20 hpf; however, an additional delay emerges at this
time. Notably, this second phase of the delay correlates with
hoxc13b expression pattern becoming restricted to the tail bud
(Thummel, 2004).
Hox and Cdx transcription factors regulate embryonic positional identities. Cdx mutant mice display posterior body truncations of the axial skeleton, neuraxis, and caudal urorectal structures. This study shows that trunk Hox genes stimulate axial extension, as they can largely rescue these Cdx mutant phenotypes. Conversely, posterior (paralog group 13) Hox genes can prematurely arrest posterior axial growth when precociously expressed. These data suggest that the transition from trunk to tail Hox gene expression successively regulates the construction and termination of axial structures in the mouse embryo. Thus, Hox genes seem to differentially orchestrate posterior expansion of embryonic tissues during axial morphogenesis as an integral part of their function in specifying head-to-tail identity. In addition, evidence is presented that Cdx and Hox transcription factors exert these effects by controlling Wnt signaling. Concomitant regulation of Cyp26a1 expression, restraining retinoic acid signaling away from the posterior growth zone, may likewise play a role in timing the trunk-tail transition (Young, 2009).
Hox genes are essential for the patterning of the axial skeleton. Hox group 10 has been shown to specify the lumbar domain by setting a rib-inhibiting program in the presomitic mesoderm (PSM). Mice have been produced with ribs in every vertebra by ectopically expressing Hox group 6 in the PSM, indicating that Hox genes are also able to specify the thoracic domain. The information provided by Hox genes to specify rib-containing and rib-less areas is first interpreted in the myotome through the regional-specific control of Myf5 and Myf6 expression. This information is then transmitted to the sclerotome by a system that includes FGF and PDGF signaling to produce vertebrae with or without ribs at different axial levels. These findings offer a new perspective of how Hox genes produce global patterns in the axial skeleton and support a redundant nonmyogenic role of Myf5 and Myf6 in rib formation (Vinagre, 2010).
Abdominal-B homologs and spinal cord development Hoxd10 expression has been used as a primary marker of the lumbosacral (LS) region of the spinal cord to examine the early programming of regional characteristics within the posterior spinal cord of the chick embryo. Hoxd10 is uniquely expressed at a high level in the lumbosacral cord, from the earliest stages of motor column formation through stages of motoneuron axon outgrowth. To define the time period when this gene pattern is determined, Hoxd10 expression was assessed after transposition of lumbosacral and thoracic (T) segments at early neural tube stages. Evidence is presented that there is an early prepattern for Hoxd10 expression in the lumbosacral neural tube; a prepattern that is established at or before stages of neural tube closure. Cells within more posterior lumbosacral segments have a greater ability to develop high level Hoxd10 expression than the most anterior lumbosacral segments or thoracic segments. During subsequent neural tube stages, this prepattern is amplified and stabilized by environmental signals such that all lumbosacral segments acquire the ability to develop high levels of Hoxd10, independent of their axial environment. Results from experiments in which posterior neural segments and/or paraxial mesoderm segments were placed at different axial levels suggest that signals setting Hoxd10 expression form a decreasing posterior-to-anterior gradient. These experiments do not, however, implicate adjacent paraxial mesoderm as the only source of graded signals. It is suggested, instead, that signals from more posterior embryonic regions influence Hoxd10 expression after the early establishment of a regional prepattern. Concurrent analyses of patterns of LIM proteins and motor column organization after experimental surgeries suggest that the programming of these characteristics follows similar rules (Lance-Jones, 2001).
A central conclusion to be drawn from these experiments is that the specification of regional characteristics within prospective T and LS segments begins before or at
the time of neural tube closure (stage 11 for T segments, stage 13 for anterior LS segments). Stage 13 LS neural tube segments show two distinctive characteristics.
(1) Anterior LS segments (LS1-3) are capable of developing high levels of Hoxd10 even when placed in posterior T regions at stage 13. No such high level
expression ever develops in posterior T segments. (2) Posterior LS2-LS3 (but not LS1-anterior LS2) can develop at least some level of Hoxd10 expression
when placed in anterior T regions at stage 13. As in the normal LS cord, a gradient of Hoxd10 expression is evident in displaced LS segments with the originally
most-posterior segment showing the highest level of expression. In marked contrast, stage 11-13 T segments are distinguished by their inability to develop high levels
of Hoxd10 expression after displacement to LS regions. Only when placed in middle to posterior LS regions, do stage 11-13 T segments occasionally express
LS-like levels of Hoxd10 (Lance-Jones, 2001).
To address the expression and function of Hoxb13 (the 5' most Hox gene in the HoxB cluster) mice have been generated with loss-of-function and ß-galactosidase reporter insertion alleles of this gene. Mice homozygous for Hoxb13 loss-of-function mutations show overgrowth in all major structures derived from the tail bud, including the developing secondary neural tube (SNT), the caudal spinal ganglia, and the caudal vertebrae. Using the ß-galactosidase reporter allele of Hoxb13, also a loss-of-function allele, it was found that the expression patterns of Hoxb13 in the developing spinal cord and caudal mesoderm are closely associated with overgrowth phenotypes in the tails of homozygous mutant animals. These phenotypes can be explained by the observed increased cell proliferation and decreased levels of apoptosis within the tail of homozygous mutant mice. This analysis of Hoxb13 function suggests that this 5' Hox gene may act as an inhibitor of neuronal cell proliferation, an activator of apoptotic pathways in the SNT, and as a general repressor of growth in the caudal vertebrae (Economides, 2003b).
Studies of the programming of Hox patterns at anterior spinal levels suggest that these events are accomplished through an integration of Hensen's node-derived and paraxial mesoderm signaling. In vivo tissue manipulation in the avian embryo was used to examine the respective roles of node- derived and other local signals in the programming of a Hox pattern at posterior spinal levels. Hoxd10 is highly expressed in the lumbosacral (LS) spinal cord and adjacent paraxial mesoderm. At stages of LS neural tube formation (stages 12-14), the tailbud contains the remnants of Hensen's node and the primitive streak. Hoxd10 expression was analyzed after transposition of LS neural segments with and without the tailbud, after isolation of normally positioned LS segments from the stage 13 tailbud, and after axial displacement of posterior paraxial mesoderm. Data suggest that inductive signals from the tailbud are primarily responsible for the programming of Hoxd10 at neural plate and the earliest neural tube stages. After these stages, the LS neural tube appears to differ from more anterior neural segments in its lack of dependence on Hox-inductive signals from local tissues, including paraxial mesoderm. The data also suggest that a graded system of repressive signals for posterior Hox genes is present at cervical and thoracic levels and likely to originate from paraxial mesoderm (Omelchenko, 2003).
Expression of Hoxa10 in the presomitic mesoderm is sufficient to confer a Hox group 10 patterning program to the somite, producing vertebrae without ribs, an effect not achieved when Hoxa10 is expressed in the somites. In addition, Hox group 11-dependent vertebral sacralization requires Hoxa11 expression in the presomitic mesoderm, while their caudal differentiation requires that Hoxa11 is expressed in the somites. Therefore, Hox gene patterning activity is different in the somites and presomitic mesoderm, the latter being very prominent for Hox gene-mediated patterning of the axial skeleton. This is further supported by the finding that inactivation of Gbx2, a homeobox-containing gene expressed in the presomitic mesoderm but not in the somites, produces Hox-like phenotypes in the axial skeleton without affecting Hox gene expression (Carapuco, 2005).
In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb levels are, however, not well understood. This study shows that a single Hox gene, Hoxc9, has an essential role in organizing the motor system through global repressive activities. Hoxc9 is required for the generation of thoracic motor columns, and in its absence, neurons acquire the fates of limb-innervating populations. Unexpectedly, multiple Hox genes are derepressed in Hoxc9 mutants, leading to motor pool disorganization and alterations in the connections by thoracic and forelimb-level subtypes. Genome-wide analysis of Hoxc9 binding suggests that this mode of repression is mediated by direct interactions with Hox regulatory elements, independent of chromatin marks typically associated with repressed Hox genes (Jung, 2010).
Abdominal-B homologs and skin The expression patterns of two distantly clustered Hox genes were studied:cHoxc-8, a median
paralog, and cHoxd-13, located at the 5' extremity of the HoxD cluster. These could, respectively, be involved
in specification of dorsal feather- and foot scale-forming skin in the chick embryo. The cHoxc-8 transcripts are
present at embryonic day 3.5 (E3.5) in the somitic cells, which give rise to the dorsal dermis by E5, and
at E6.5-8.5 in the dorsal dermal and epidermal cells during the first stages of feather morphogenesis.
The cHoxd-13 transcripts are present at E4.5-9.5 in the autopodial mesenchyme and at E10.5-12.5 in
the plantar dermis during the initiation of reticulate scale morphogenesis. Both the cHoxc-8 and
cHoxd-13 transcripts are no longer detectable after the anlagen stage of cutaneous appendage
morphogenesis. Heterotopic dermal-epidermal recombinations of dorsal, plantar, and
apteric tissues reveal that the epidermal ability or inability to form feathers is already established by
the time of skin formation. Retinoic acid (RA) treatment at E11 induces after 12 hr an inhibition of
cHoxd-13 expression in the plantar dermis, followed by the formation of feather filaments on the
reticulate scales. When E7.5 dorsal explants are treated with RA for 6 days, they form scale-like
structures where the Hox transcripts are no longer detectable. Protein analysis reveals that the plantar
filaments, made up of feather beta-keratins, correspond to a homeotic transformation, whereas the
scale-like structures, composed also of feather beta-keratins, are teratoid. These results strengthen
the hypothesis that different homeobox genes play a significant role in specifying the regional identity of
the different epidermal territories (Kanzler, 1997).
Hox genes are usually expressed temporally and spatially in a colinear manner with respect to their
positions in the Hox complex. Consistent with the expected pattern for a paralogous group 13 member,
early embryonic Hoxc13 expression is found in the nails and tail. Hoxc13 is also expressed in vibrissae,
in the filiform papillae of the tongue, and in hair follicles throughout the body; these are patterns that apparently
violate spatial colinearity. Mice carrying mutant alleles of Hoxc13 have been generated by gene
targeting. Homozygotes have defects in every region in which gene expression is seen. The most
striking defect is brittle hair resulting in alopecia (hairless mice). One explanation for this novel role is
that Hoxc13 has been recruited for a function common to hair, nail, and filiform papilla development (Godwin, 1998).
Subclasses of motor neurons are generated at different positions along the rostrocaudal axis of the spinal cord. One feature of the rostrocaudal organization of spinal motor neurons is a position-dependent expression of Hox genes, but little is known about how this aspect of motor neuron (MN) subtype identity is assigned. The expression profile of Hox-c proteins has been used to define the source and identity of patterning signals that impose motor neuron positional identity along the rostrocaudal axis of the spinal cord. Evidence has been provided that the convergent activities of FGFs, Gdf11, and retinoid signals originating from Hensen's node (HN) and paraxial mesoderm establish and refine the Hox-c positional identity of motor neurons in the developing spinal cord (Liu, 2001).
Signals from prospective axial mesodermal tissues, HN and the primitive streak, appear to induce Hox-c expression in MNs in a position-appropriate manner. Thus, HN tissue from embryos of progressively older stages induces a profile of Hox-c expression characteristic of progressively more caudal levels of the spinal cord. These findings extend previous observations that HN has age-dependent activities in specifying the fate of cells at midbrain and hindbrain levels of the neural axis. With the exception of Hoxc5, Hox-c inductive activity is largely confined to HN and the newly formed notochord (Liu, 2001).
The profile of Hox-c inductive activity exhibited by HN coincides well with the expression pattern of FGF genes, notably Fgf8. FGFs act in vitro in a graded manner, with higher concentrations of FGFs inducing a progressively more caudal profile of neural Hox-c expression. Similarly, activation of FGF receptor signaling in vivo induces a rostral-to-caudal shift in the profile of Hox-c expression. Not all ectopic Hoxc9+ and Hoxc10+ cells located in the ventral spinal cord express MN markers, which may indicate additional actions of high level FGF signaling on MN differentiation. Nevertheless, together these in vitro and in vivo findings indicate that graded FGF signals derived from HN are likely to initiate the neural pattern of Hox-c expression. Such graded signaling could be achieved by a stage-dependent increase in the level of FGF signaling from HN since the level of Fgf8 expression in HN appears to increase in older embryos. Alternatively, since neural cells fated to give rise to progressively more caudal regions of the spinal cord are positioned close to HN for progressively longer periods, they may be exposed to the same level of FGF signaling as cells destined to populate more rostral regions of the spinal cord, but for a longer period. Recent studies have provided evidence that FGF signaling within HN promotes the proliferation of prospective neural cells, maintaining a progenitor cell population throughout the period of spinal cord elongation. Thus, FGF signaling within HN may coordinate the proliferation and R-C specification of spinal progenitor cells (Liu, 2001).
The onset of expression of the Hox-c proteins by spinal MNs occurs after neurons have left the cell cycle, yet patterned Hox-c expression is specified at the time of neural plate formation. How is the early specification of positional identity linked to the expression of Hox-c proteins in MNs? In Xenopus, the FGF-dependent regulation of Hox gene expression in mesodermal and neural cells involves Cdx genes. Different members of Cdx gene family appear to be expressed at different R-C levels during early stages of chick neural development. Thus, Cdx genes are plausible mediators of FGF signaling in the regulation of Hox-c expression within MNs.
Many aspects of the R-C pattern of Hox-c expression in spinal MNs can be accounted for by the action of FGFs provided by HN. But three observations indicate that additional signals are required to achieve the profile of Hox-c expression evident at cervical and lumbar levels. (1) Neither HN nor FGFs induce the neural expression of Hoxc5, a Hox-c protein that delineates cervical levels of the spinal cord. (2) Segments of the thoracic neural tube isolated after the influence of HN-derived signals exhibit ectopic caudal expression of Hoxc6, suggesting that the normal caudal limit of Hoxc6 expression is defined by signals that act later than those provided by HN. (3) Hoxc10 expression is induced only at very high FGF concentrations, suggesting that the acquisition of a caudal Hox-c profile requires additional signals (Liu, 2001).
One source of these additional signals appears to be the paraxial mesoderm. Paraxial mesodermal signals refine the R-C pattern of neuronal Hox-c expression initiated by FGF signals from the primitive streak and HN. Rostral paraxial mesoderm expresses high levels of retinoid signaling activity, and retinoids rather than FGFs induce the expression of Hoxc5 at cervical levels. Retinoid signaling also refines the expression pattern of Hox-c proteins whose expression is initiated by FGF signals from HN. Retinoid signaling from rostral paraxial mesoderm therefore appears necessary to establish a cervical profile of Hox-c expression in MNs. By the time of its caudal expression, the initial specification of neural Hox-c expression has been established, and there has been a marked decrease in the competence of thoracic neural tissue to respond to retinoid signaling with changes in Hox-c expression (unpublished observations). At these more caudal levels, HN and the paraxial mesoderm selectively expresses Gdf11, a member of the TGFß family. Gdf11 alone appears to have little Hox-c-inducing ability, but in conjunction with FGF signaling, markedly alters the profile of Hox-c expression. The prominent expression of Hoxc9 and Hoxc10 normally observed at caudal thoracic and rostral lumbar levels of the spinal cord may therefore be achieved through the joint exposure of neural cells to FGFs and Gdf11 (Liu, 2001).
Abdominal-B homologs and mammary gland
Although the role of Hox genes in patterning the mammalian body plan has been studied extensively
during embryonic and fetal development, relatively little is known concerning Hox gene function in adult
animals. Analysis of mice with mutant Hoxa9, Hoxb9, and Hoxd9 genes shows that these paralogous
genes are required for mediating the expansion and/or differentiation of the mammary epithelium ductal
system in response to pregnancy. Mothers with these three mutant genes cannot raise their own pups, but
the pups can be rescued if fostered by wild-type mothers. Histologically, the mammary glands of the
mutant mothers seem normal before pregnancy but do not develop properly in response to pregnancy and
parturition. Hoxa9, Hoxb9, and Hoxd9 are expressed normally in adult mammary glands, suggesting a
direct role for these genes in the development of mammary tissue after pregnancy. Because
loss-of-function mutations in these Hox genes cause hypoplasia of the mammary gland after pregnancy, it
may be productive to look for misexpression of these genes in mammary carcinomas (Chen, 1999).
Abdominal-B homologs and uterus Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri-implantation period,
Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation
by ovarian steroids, prompted a test to see whether estrogen and progesterone directly regulate the expression of Hoxa-10 and other AbdB Hoxa genes. Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist
RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner.
Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by
estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position
within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. An examination was carried out to determine if the embryonic
expression of Hoxa10 is susceptible to regulation by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen
diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10
knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing
female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Mullerian duct. Thus, these data not only
establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the
teratogenic effects of DES on the developing reproductive tract (Ma, 1998).
The murine female reproductive tract differentiates along the anteroposterior axis during postnatal
development. This process is marked by the emergence of distinct cell types in the oviduct, uterus, cervix
and vagina and is dependent on specific mesenchymal-epithelial interactions as demonstrated by earlier
heterografting experiments. Members of the Wnt family of signaling molecules have been recently identified
in this system and an early functional role in reproductive tract development has been demonstrated. Mice
were generated using ES-mediated homologous recombination for the Wnt-7a gene. Since Wnt-7a is expressed in the female reproductive tract, the developmental consequences of lack of Wnt-7a in the female reproductive tract was examined. The oviduct is found to lack a clear demarcation from the anterior uterus, and it acquires several cellular and
molecular characteristics of the uterine horn. The uterus acquires cellular and molecular characteristics that
represent an intermediate state between normal uterus and vagina. Normal vaginas have a stratified epithelium
and normal uteri have a simple columnar epithelium, however, mutant uteri have stratified epithelium.
Additionally, Wnt-7a mutant uteri do not form glands. The changes observed in the oviduct and uterus are
accompanied by a postnatal loss of hoxa-10 and hoxa-11 expression, revealing that Wnt-7a is not required
for early hoxa gene expression, but is required for maintenance of expression. These clustered hox genes
have been shown to play a role in anteroposterior patterning in the female reproductive tract. In addition to
this global posterior shift in the female reproductive tract, the uterine smooth muscle was found to be
disorganized, indicating development along the radial axis is affected. Changes in the boundaries and levels
of other Wnt genes are detectable at birth, prior to changes in morphologies. These results suggest that a
mechanism exists whereby Wnt-7a signaling from the epithelium maintains the molecular and morphological
boundaries of distinct cellular populations along the anteroposterior and radial axes of the female
reproductive tract (Miller, 1998).
The murine prostate is a structure that is made up of four distinct lobes; the dorsal and lateral prostates (often grouped together as the dorsolateral prostate), the anterior (coagulating gland) and the ventral prostate. Hox genes have been implicated in the development of these structures, but how each lobe acquires unique identities for specific functions has not been addressed. In this study, the ventral prostate-specific function of Hoxb13 is described. Mice lacking Hoxb13 function show normal numbers of duct tips, but mice mutant for both Hoxb13 and Hoxd13 exhibit severe hypoplasia of the duct tips, revealing a role for Hoxb13 in ventral prostate morphogenesis. Additionally, a ventral lobe-specific defect was identified in Hoxb13 mutants wherein the epithelium is composed of simple cuboidal cells rather than of tall columnar cells. Ventral prostate ducts appear devoid of contents and do not express the ventral prostate-specific secretory proteins p12, a kazal-type protease inhibitor and p25, a spermine binding protein. These defects are not due to reduction of Nkx3.1 expression or to a global effect on androgen receptor signaling. These results suggest a specific role for Hoxb13 in a differentiation pathway that gives the ventral prostate epithelium a unique identity, as well as a more general role in ventral prostate morphogenesis that is redundant with other Hox13 paralogs (Economides, 2003a).
The mammalian Hox complex is divided into four linkage
groups containing 13 sets of paralogous genes. These paralogous genes have retained functional redundancy during evolution. For this reason,
loss of only one or two Hox genes within a paralogous group
often results in incompletely penetrant phenotypes which are difficult
to interpret by molecular analysis. For example, mice individually
mutant for Hoxa11 or Hoxd11 show no discernible kidney
abnormalities. Hoxa11/Hoxd11 double mutants, however,
demonstrate hypoplasia of the kidneys. Removal of the last Hox11 paralogous member, Hoxc11, results in the complete loss of metanephric kidney induction. In these triple mutants, the metanephric blastema condenses, and expression of early patterning genes, Pax2 and Wt1, is unperturbed.
Eya1 expression is also intact. Six2 expression,
however, is absent, as is expression of the inducing growth factor,
Gdnf. In the absence of Gdnf, ureteric bud formation is
not initiated. Molecular analysis of this phenotype demonstrates that
Hox11 control of early metanephric induction is accomplished by
the interaction of Hox11 genes with the pax-eya-six regulatory cascade, a pathway that may be used by Hox genes more generally for the induction of multiple structures along the anteroposterior axis (Willik, 2002).
The genetic control of cell fate specification, morphogenesis and expansion
of the spleen, a crucial lymphoid organ, is poorly understood. Recent studies
of mutant mice implicate various transcription factors in spleen development,
but the hierarchical relationships between these factors have not been
explored. This report establishes a genetic network that regulates spleen
ontogeny, by analyzing asplenic mice mutant for the transcription factors
Pbx1, Hox11 (Tlx1), Nkx3.2 (Bapx1) and Pod1 (capsulin, Tcf21).
Hox11 and Nkx2.5, among the earliest known markers for
splenic progenitor cells, are absent in the splenic anlage of Pbx1
homozygous mutant (-/-) embryos, implicating the TALE homeoprotein
Pbx1 in splenic cell specification. Pbx1 and Hox11
genetically interact in spleen formation and loss of either is associated with
a similar reduction of progenitor cell proliferation and failed expansion of
the splenic anlage. Chromatin immunoprecipitation assays show that Pbx1 binds
to the Hox11 promoter in spleen mesenchymal cells, which co-express
Pbx1 and Hox11. Furthermore, Hox11 binds its own promoter in
vivo and acts synergistically with TALE proteins to activate transcription,
supporting its role in an auto-regulatory circuit. These studies establish a
Pbx1-Hox11-dependent genetic and transcriptional pathway in
spleen ontogeny. Additionally, it is demonstrated that while Nkx3.2 and
Pod1 control spleen development via separate pathways, Pbx1
genetically regulates key players in both pathways, and thus emerges as a
central hierarchical co-regulator in spleen genesis (Brendolan, 2005).
In humans and mice, mutations in Hoxa13 cause malformation of limb and genitourinary (GU) regions. In males, one of the most common GU malformations associated with loss of Hoxa13 function is hypospadia, a condition defined by the poor growth and closure of the urethra and glans penis. By examining early signaling in the developing mouse genital tubercle, Hoxa13 has been found to be essential for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium. In Hoxa13GFP-mutant mice, hypospadias occur as a result of the combined loss of Fgf8 and Bmp7 expression in the urethral plate epithelium, as well as the ectopic expression of noggin (Nog) in the flanking mesenchyme. In vitro supplementation with Fgf8 restores proliferation in homozygous mutants to wild-type levels, suggesting that Fgf8 is sufficient to direct early proliferation of the developing genital tubercle. However, the closure defects of the distal urethra and glans can be attributed to a loss of apoptosis in the urethra, which is consistent with reduced Bmp7 expression in this region. Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling. Finally, a novel role for Hoxa13 in the vascularization of the glans penis is also identified (Morgan, 2003).
Abdominal-B homologs and endoderm development Hoxa11 and Hoxd11 are functionally redundant during kidney development. Mice with homozygous null mutation of either gene have normal kidneys, but double mutants have rudimentary, or in extreme cases, absent kidneys. The mechanism for renal growth failure has been examined in this mouse model and defects in ureteric bud branching morphogenesis have been found. The ureteric buds are either unbranched or have an atypical pattern characterized by lack of terminal branches in the midventral renal cortex. The mutant embryos show that Hoxa11 and Hoxd11 control development of a dorsoventral renal axis. By immunohistochemical analysis, Hoxa11 expression is restricted to the early metanephric mesenchyme, which induces ureteric bud formation and branching. It is not found in the ureteric bud. This suggests that the branching defect is caused by failure of mesenchyme to epithelium signaling. In situ hybridizations with Wnt7b, a marker of the metanephric kidney, show that the branching defect is not simply the result of homeotic transformation of metanephros to mesonephros. Absent Bf2 and Gdnf expression in the midventral mesenchyme, these findings, which alone could account for branching defects, show that Hoxa11 and Hoxd11 are necessary for normal gene expression in the ventral mesenchyme. Attenuation of normal gene expression, along with the absence of a detectable proliferative or apoptotic change in the mutants, shows that one function of Hoxa11 and Hoxd11 in the developing renal mesenchyme is to regulate differentiation necessary for mesenchymal-epithelial reciprocal inductive interactions (Patterson, 2001).
Hoxa13 is expressed early in the caudal mesoderm and endoderm of the developing hindgut. The tissue-specific roles of Hoxa13 function have not been described. Hand-foot-genital syndrome, a rare dominantly inherited human malformation syndrome characterized by distal extremity and genitourinary anomalies, is caused by mutations in the HOXA13 gene. Evidence is presented that one specific HOXA13 mutation likely acts as a dominant negative in vivo. When chick HFGa13 is overexpressed in the chick caudal endoderm early in development, caudal structural malformations occur. The phenotype is specific to HFGa13 expression in the posterior endoderm, and includes taillessness and severe gut/genitourinary (GGU) malformations. Chick HFGa13 negatively regulates expression of Hoxd13 and antagonizes functions of both endogenous Hoxa13 and Hoxd13 proteins. A fundamental role is suggested for epithelial specific expression of Hoxa13 in the epithelial-mesenchymal interaction necessary for tail growth and posterior GGU patterning (de Santa Barbaram, 2002).
Inactivating mutations in the tumor suppressor gene MEN1 cause the inherited cancer syndrome multiple endocrine neoplasia type 1 (MEN1). The ubiquitously expressed MEN1 encoded protein, menin, interacts with MLL (mixed-lineage leukemia protein), and together they are essential components of a multiprotein complex with histone methyl transferase activity. MLL is also essential for hematopoiesis, and plays a critical role in leukemogenesis via epigenetic regulation of Hoxa9 expression that also requires menin. Therefore, the role of menin in hematopoiesis was investigated. Men1-/- embryonic stem (ES) cell lines were induced to differentiate in vitro. While these cells were able to form embryoid bodies (EBs) expressing the early markers Flk-1 and c-Kit, their ability to further differentiate into hematopoietic colonies was compromised. The Men1-/- ES cells show reduced expression of Hoxa9 that can be recovered by reexpression of Menin. The block in differentiation of Men1-/- ES cell lines can be rescued not only by the expression of menin but also that of Hoxa9. These results suggest that, similar to MLL, menin is required for hematopoiesis, and this requirement may be mediated through regulation of Hoxa9 expression (Novotny, 2009).
Transcriptional deregulation through the production of dominant-acting chimeric transcription factors derived from chromosomal translocations is a common theme in the pathogenesis of acute leukemias; however, the essential target genes for acute leukemogenesis are unknown. Primary myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which is also expressed in the myeloid clonogenic progenitor fraction of normal bone marrow. Continued maintenance of this MLL-dependent Hoxa gene expression profile is associated with conditional MLL-associated myeloid immortalization. Moreover, Hoxa7 and Hoxa9 are specifically required for efficient in vitro myeloid immortalization by an MLL fusion protein but not other leukemogenic fusion proteins. In a bone marrow transduction/transplantation model, Hoxa9 is essential for MLL-dependent leukemogenesis in vivo, a primary requirement detected at the earliest stages of disease initiation. Thus, a genetic reliance on Hoxa7 and Hoxa9 in MLL-mediated transformation demonstrates a gain-of-function mechanism for MLL oncoproteins as upstream constitutive activators that promote myeloid transformation via a Hox-dependent mechanism (Ayton, 2003).
Homeobox transcription factors Meis1 and Hoxa9 promote hematopoietic progenitor self-renewal and cooperate to cause acute myeloid leukemia (AML). While Hoxa9 alone blocks the differentiation of nonleukemogenic myeloid cell-committed progenitors, coexpression with Meis1 is required for the production of AML-initiating progenitors, which also transcribe a group of hematopoietic stem cell genes, including Cd34 and Flt3 (defined as Meis1-related leukemic signature genes). This study used dominant trans-activating (Vp16 fusion) or trans-repressing (engrailed fusion) forms of Meis1 to define its biochemical functions that contribute to leukemogenesis. Surprisingly, Vp16-Meis1 (but not engrailed-Meis1) functioned as an autonomous oncoprotein that mimicked combined activities of Meis1 plus Hoxa9, immortalizing early progenitors, inducing low-level expression of Meis1-related signature genes, and causing leukemia without coexpression of exogenous or endogenous Hox genes. Vp16-Meis1-mediated transformation required the Meis1 function of binding to Pbx and DNA but not its C-terminal domain (CTD). The absence of endogenous Hox gene expression in Vp16-Meis1-immortalized progenitors allowed investigation of how Hox alters gene expression and cell biology in early hematopoietic progenitors. Strikingly, expression of Hoxa9 or Hoxa7 stimulated both leukemic aggressiveness and transcription of Meis1-related signature genes in Vp16-Meis1 progenitors. Interestingly, while the Hoxa9 N-terminal domain (NTD) is essential for cooperative transformation with wild-type Meis1, it is dispensable in Vp16-Meis1 progenitors. The fact that a dominant transactivation domain fused to Meis1 replaces the essential functions of both the Meis1 CTD and Hoxa9 NTD suggests that Meis-Pbx and Hox-Pbx (or Hox-Pbx-Meis) complexes co-occupy cellular promoters that drive leukemogenesis and that Meis1 CTD and Hox NTD cooperate in gene activation. Chromatin immunoprecipitation confirmed co-occupancy of Hoxa9 and Meis1 on the Flt3 promoter (Wang, 2006 full test of article).
Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain (Nguyen, 2009).
The emergence of limb-driven locomotor behaviors was a key event in the evolution of vertebrates and fostered the transition from aquatic to terrestrial life. This study showed that the generation of limb-projecting lateral motor column (LMC) neurons in mice relies on a transcriptional autoregulatory module initiated via transient activity of multiple genes within the HoxA and HoxC clusters. Repression of this module at thoracic levels restricts expression of LMC determinants, thus dictating LMC position relative to the limbs. This suppression is mediated by a key regulatory domain that is specifically found in the Hoxc9 proteins of appendage-bearing vertebrates. The profile of Hoxc9 expression inversely correlates with LMC position in land vertebrates and likely accounts for the absence of LMC neurons in limbless species such as snakes. Thus, modulation of both Hoxc9 protein function and Hoxc9 gene expression likely contributed to evolutionary transitions between undulatory and ambulatory motor circuit connectivity programs (Jung, 2014).
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Previous studies have implicated early retinoid signaling in establishing the generic character of the spinal cord, and later retinoid signaling in defining the pattern of Hox gene expression in the developing hindbrain (Liu, 2001).
Abdominal-B:
Biological Overview
| Promoter Structure
| Transcriptional Regulation
| Targets of activity
| Protein Interactions
| Developmental Biology
| Effects of Mutation
| References
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