Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract

Hox genes play a fundamental role in the establishment of chordate body plan, especially in the anteroposterior patterning of the nervous system. Particularly interesting are the anterior groups of Hox genes (Hox1-Hox4) since their expression is coupled to the control of regional identity in the anterior regions of the nervous system, where the highest structural diversity is observed. Ascidians, among chordates, are considered a good model to investigate evolution of Hox gene, organisation, regulation and function. We report here the cloning and the expression pattern of CiHox3, a Ciona intestinalis anterior Hox gene homologous to the paralogy group 3 genes. In situ hybridization at the larva stage revealed that CiHox3 expression was restricted to the visceral ganglion of the central nervous system. The presence of a sharp posterior boundary and the absence of transcript in mesodermal tissues are distinctive features of CiHox3 expression when compared to the paralogy group 3 in other chordates. We have investigated the regulatory elements underlying CiHox3 neural-specific expression and, using transgenic analysis, we were able to isolate an 80 bp enhancer responsible of CiHox3 activation in the central nervous system (CNS). A comparative study between mouse and Ciona Hox3 promoters demonstrated that divergent mechanisms are involved in the regulation of these genes in vertebrates and ascidians.

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Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract

Development ◽

10.1242/dev.125.16.3201 ◽

1998 ◽

Vol 125 (16) ◽

pp. 3201-3211 ◽

Cited By ~ 2

Author(s):

C. Miller ◽

D.A. Sassoon

Keyword(s):

Reproductive Tract ◽

Hox Genes ◽

Cell Types ◽

Female Reproductive Tract ◽

Molecular Characteristics ◽

Anteroposterior Patterning ◽

Stratified Epithelium ◽

Distinct Cell ◽

Hoxa Gene Expression ◽

Posterior Shift

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 upon 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 (Parr, B. A. and McMahon, A. P. (1995) Nature 374, 350–353). Since Wnt-7a is expressed in the female reproductive tract, we examined the developmental consequences of lack of Wnt-7a in the female reproductive tract. We observe that the oviduct lacks a clear demarcation from the anterior uterus, and 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 stratified epithelium and normal uteri have 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, we note that the uterine smooth muscle is 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 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.

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The Role of HOX Genes in the Development and Function of the Female Reproductive Tract

Seminars in Reproductive Medicine ◽

10.1055/s-2000-13478 ◽

2000 ◽

Vol 18 (01) ◽

pp. 081-090 ◽

Cited By ~ 56

Author(s):

Hugh S. Taylor

Keyword(s):

Reproductive Tract ◽

Hox Genes ◽

Female Reproductive Tract ◽

And Function

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Expression of ovarian tumour suppressor OPCML in the female CD-1 mouse reproductive tract

Reproduction ◽

10.1530/rep-08-0511 ◽

2009 ◽

Vol 137 (4) ◽

pp. 721-726

Author(s):

Jean S Fleming ◽

H James McQuillan ◽

Melanie J Millier ◽

Grant C Sellar

Keyword(s):

Reproductive Tract ◽

Reproductive Function ◽

Ovarian Surface Epithelium ◽

Ovarian Tumour ◽

Surface Epithelium ◽

Cell Of Origin ◽

Ductal Cells ◽

Ovarian Cancers ◽

Opioid Binding ◽

Protein Cell

Opioid binding protein/cell adhesion molecule-like gene (OPCML) is frequently inactivated in epithelial ovarian cancer, but the role of this membrane protein in normal reproductive function is unclear. The ovarian surface epithelium (OSE) is thought to be the cell of origin of most epithelial ovarian cancers, some of which arise after transformation of OSE cells lining ovarian inclusion cysts, formed during ovulation. We used immunohistochemistry, immunoblotting and quantitative RT-PCR (qRT-PCR) to investigate OPCML expression in the uteri and ovaries of cycling 3-month CD-1 mice, as well as in ovaries from older mice containing inclusion cysts derived from rete ovarii tubules. Immunoblotting showed OPCML bands in uterine, but not whole ovarian or muscle extracts. Strong OPCML immunoreactivity was observed in oviduct, rete ovarii and uterus, whereas in ovary more immunoreactivity was seen in granulosa cells than OSE. No staining was observed in OSE around ovulation sites, where OSE cells divide to cover the site. OPCML immunoreactivity was also weaker in more dysplastic cells lining large ovarian inclusion cysts, compared with normal rete ovarii. No significant changes inOpcmlmRNA expression were observed in whole ovarian and uterine extracts at different stages of the cycle. We conclude that murine OPCML is more consistently expressed in cells lining the uterus, oviduct and rete ovarii than in ovary and is not expressed in OSE associated with ovulation sites. This observation supports the hypothesis that a proportion of epithelial ovarian cancers arise from ductal cells and other epithelia of the secondary Mullerian system, rather than the OSE.

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Zebrafish hox genes: genomic organization and modified colinear expression patterns in the trunk

Development ◽

10.1242/dev.125.3.407 ◽

1998 ◽

Vol 125 (3) ◽

pp. 407-420 ◽

Cited By ~ 20

Author(s):

V.E. Prince ◽

L. Joly ◽

M. Ekker ◽

R.K. Ho

Keyword(s):

Hox Genes ◽

Genomic Organization ◽

Expression Patterns ◽

Regional Identity ◽

Hoxa Cluster ◽

Hox Cluster ◽

Sequence Homologies ◽

Race Pcr ◽

Linkage Relationships ◽

Hox Clusters

The Hox genes are implicated in conferring regional identity to the anteroposterior axis of the developing embryo. We have characterized the organization and expression of hox genes in the teleost zebrafish (Danio rerio), and compared our findings with those made for the tetrapod vertebrates. We have isolated 32 zebrafish hox genes, primarily via 3′RACE-PCR, and analyzed their linkage relationships using somatic cell hybrids. We find that in comparison to the tetrapods, zebrafish has several additional hox genes, both within and beyond the expected 4 hox clusters (A-D). For example, we have isolated a member of hox paralogue group 8 lying on the hoxa cluster, and a member of hox paralogue group 10 lying on the b cluster, no equivalent genes have been reported for mouse or human. Beyond the 4 clusters (A-D) we have isolated a further 3 hox genes (the hoxx and y genes), which according to their sequence homologies lie in paralogue groups 4, 6, and 9. The hoxx4 and hoxx9 genes occur on the same set of hybrid chromosomes, hinting at the possibility of an additional hox cluster for the zebrafish. Similar to their tetrapod counterparts, zebrafish hox genes (including those with no direct tetrapod equivalent) demonstrate colinear expression along the anteroposterior (AP) axis of the embryo. However, in comparison to the tetrapods, anterior hox expression limits are compacted over a short AP region; some members of adjacent paralogue groups have equivalent limits. It has been proposed that during vertebrate evolution, the anterior limits of Hox gene expression have become dispersed along the AP axis allowing the genes to take on novel patterning roles and thus leading to increased axial complexity. In the teleost zebrafish, axial organization is relatively simple in comparison to that of the tetrapod vertebrates; this may be reflected by the less dispersed expression domains of the zebrafish hox genes.

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Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Journal of Developmental Biology ◽

10.3390/jdb10010004 ◽

2022 ◽

Vol 10 (1) ◽

pp. 4

Author(s):

Zainab Afzal ◽

Robb Krumlauf

Keyword(s):

Transcriptional Regulation ◽

Molecular Mechanisms ◽

Hox Genes ◽

Regional Identity ◽

Regulatory Mechanisms ◽

Regulation Of Transcription ◽

Axial Patterning ◽

Hox Gene ◽

Molecular Framework ◽

Combinatorial Code

Hox genes play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. Nested domains of Hox expression generate a combinatorial code that provides a molecular framework for specifying the properties of tissues along the A–P axis. Hence, it is important to understand the regulatory mechanisms that coordinately control the precise patterns of the transcription of clustered Hox genes required for their roles in development. New insights are emerging about the dynamics and molecular mechanisms governing transcriptional regulation, and there is interest in understanding how these may play a role in contributing to the regulation of the expression of the clustered Hox genes. In this review, we summarize some of the recent findings, ideas and emerging mechanisms underlying the regulation of transcription in general and consider how they may be relevant to understanding the transcriptional regulation of Hox genes.

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Functional specificity of theHoxa13homeobox

Development ◽

10.1242/dev.128.16.3197 ◽

2001 ◽

Vol 128 (16) ◽

pp. 3197-3207 ◽

Cited By ~ 2

Author(s):

Yuanxiang Zhao ◽

S. Steven Potter

Keyword(s):

Reproductive Tract ◽

Hox Genes ◽

Axial Skeleton ◽

Female Reproductive Tract ◽

Functional Equivalence ◽

Functional Specificity ◽

Hoxa Cluster ◽

Downstream Targets ◽

Gene Chips ◽

Test Models

To better define Abd-B type homeodomain function, to test models that predict functional equivalence of all Hox genes and to initiate a search for the downstream targets of Hoxa13, we have performed a homeobox swap by replacing the homeobox of the Hoxa11 gene with that of theHoxa13 gene. The Hoxa11 and Hoxa13 genes are contiguous Abd-B type genes located at the 5′ end of the HoxA cluster. The modified Hoxa11 allele (A1113hd)showed near wild-type function in the development of the kidneys, axial skeleton and male reproductive tract, consistent with functional equivalence models. In the limbs and female reproductive tract, however, theA1113hd allele appeared to assume dominant Hoxa13function. The uterus, in particular, showed a striking homeotic transformation towards cervix/vagina, where Hoxa13 is normally expressed. Gene chips were used to create a molecular portrait of this tissue conversion and revealed over 100 diagnostic gene expression changes. This work identifies candidate downstream targets of the Hoxa13 gene and demonstrates that even contiguous Abd-B homeoboxes have functional specificity.

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Characterisation of the role and regulation of Ultrabithorax in sculpting fine-scale leg morphology

10.1101/2020.06.17.152918 ◽

2020 ◽

Author(s):

Alexandra D. Buffry ◽

Sebastian Kittelmann ◽

Alistair P. McGregor

Keyword(s):

Gene Regulatory Networks ◽

Regulatory Network ◽

Regulatory Networks ◽

Hox Genes ◽

Regional Identity ◽

Fine Scale ◽

Hox Gene ◽

Leg Development ◽

Gene Regulatory ◽

Leg Morphology

AbstractHox genes are expressed during embryogenesis and determine the regional identity of animal bodies along the antero-posterior axis. However, they also function post-embryonically to sculpt fine-scale morphology. To better understand how Hox genes are integrated into post-embryonic gene regulatory networks, we further analysed the role and regulation of Ultrabithorax (Ubx) during mesothoracic (T2) leg development in Drosophila melanogaster. Ubx represses leg trichomes in the proximal posterior region of the T2 femur (the so-called naked valley) and we found that it likely does so through activating the expression of microRNA-92a. We also identified a T2 leg enhancer of Ubx that recapitulates the temporal and regional activity of this Hox gene in these appendages. Analysis of motifs in this enhancer predicted that it is bound by Distal-less (Dll) and we found that knockdown of Dll results in the loss of trichomes on the T2 femur. This suggests that while Ubx activates microRNA-92a to repress trichomes in the naked valley region of the proximal femur, Dll may repress Ubx more distally to enable formation of trichomes. Taken together our results provide insights into how Ubx is integrated into a postembryonic gene regulatory network to determine fine-scale leg morphology.

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