Plasticity of transposed rhombomeres: Hox gene induction is correlated with phenotypic modifications

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 2707-2721 ◽  
Author(s):  
A. Grapin-Botton ◽  
M.A. Bonnin ◽  
L.A. McNaughton ◽  
R. Krumlauf ◽  
N.M. Le Douarin
Keyword(s):  
Gene Expression ◽  
Neural Tube ◽  
Hox Genes ◽  
Gene Expression Pattern ◽  
Fate Map ◽  
Hox Gene ◽  
Inductive Signal ◽  
New Location ◽  
Chick And Quail Embryos

In this study we have analysed the expression of Hoxb-4, Hoxb-1, Hoxa-3, Hoxb-3, Hoxa-4 and Hoxd-4 in the neural tube of chick and quail embryos after rhombomere (r) heterotopic transplantations within the rhombencephalic area. Grafting experiments were carried out at the 5-somite stage, i.e. before rhombomere boundaries are visible. They were preceeded by the establishment of the precise fate map of the rhombencephalon in order to determine the presumptive territory corresponding to each rhombomere. When a rhombomere is transplanted from a caudal to a more rostral position it expresses the same set of Hox genes as in situ. By contrast in many cases, if rhombomeres are transplanted from rostral to caudal their Hox gene expression pattern is modified. They express genes normally activated at the new location of the explant, as evidenced by unilateral grafting. This induction occurs whether transplantation is carried out before or after rhombomere boundary formation. Moreover, the fate of the cells of caudally transplanted rhombomeres is modified: the rhombencephalic nuclei in the graft develop according to the new location as shown for an r5/6 to r8 transplantation. Transplantation of 5 consecutive rhombomeres (i.e. r2 to r6), to the r8 level leads to the induction of Hoxb-4 in the two posteriormost rhombomeres but not in r2,3,4. Transplantations to more caudal regions (posterior to somite 3) result in some cases in the induction of Hoxb-4 in the whole transplant. Neither the mesoderm lateral to the graft nor the notochord is responsible for the induction. Thus, the inductive signal emanates from the neural tube itself, suggesting that planar signalling and predominance of posterior properties are involved in the patterning of the neural primordium.

Crustacean (malacostracan) Hox genes and the evolution of the arthropod trunk

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2239-2249 ◽  
Author(s):  
A. Abzhanov ◽  
T.C. Kaufman
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
The Body ◽  
Ancestral State ◽  
Porcellio Scaber ◽  
Hox Gene ◽  
Overlapping Domains ◽  
Discrete Domains

Representatives of the Insecta and the Malacostraca (higher crustaceans) have highly derived body plans subdivided into several tagma, groups of segments united by a common function and/or morphology. The tagmatization of segments in the trunk, the part of the body between head and telson, in both lineages is thought to have evolved independently from ancestors with a distinct head but a homonomous, undifferentiated trunk. In the branchiopod crustacean, Artemia franciscana, the trunk Hox genes are expressed in broad overlapping domains suggesting a conserved ancestral state (Averof, M. and Akam, M. (1995) Nature 376, 420–423). In comparison, in insects, the Antennapedia-class genes of the homeotic clusters are more regionally deployed into distinct domains where they serve to control the morphology of the different trunk segments. Thus an originally Artemia-like pattern of homeotic gene expression has apparently been modified in the insect lineage associated with and perhaps facilitating the observed pattern of tagmatization. Since insects are the only arthropods with a derived trunk tagmosis tested to date, we examined the expression patterns of the Hox genes Antp, Ubx and abd-A in the malacostracan crustacean Porcellio scaber (Oniscidae, Isopoda). We found that, unlike the pattern seen in Artemia, these genes are expressed in well-defined discrete domains coinciding with tagmatic boundaries which are distinct from those of the insects. Our observations suggest that, during the independent tagmatization in insects and malacostracan crustaceans, the homologous ‘trunk’ genes evolved to perform different developmental functions. We also propose that, in each lineage, the changes in Hox gene expression pattern may have been important in trunk tagmatization.

Hox gene induction in the neural tube depends on three parameters: competence, signal supply and paralogue group

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 849-859 ◽  
Author(s):  
A. Grapin-Botton ◽  
M.A. Bonnin ◽  
N.M. Douarin Le
Keyword(s):  
Gene Expression ◽  
Neural Tube ◽  
Hox Genes ◽  
Gene Induction ◽  
Paraxial Mesoderm ◽  
Environmental Cues ◽  
Hox Gene ◽  
Anteroposterior Axis ◽  
Gene Regulatory ◽  
Genomic Clusters

It has been previously shown that Hox gene expression in the rhombencephalon is controlled by environmental cues. Thus posterior transposition of anterior rhombomeres to the r7/8 level results in the activation of Hox genes of the four first paralog groups and in homeotic transformations of the neuroepithelial fate according to its position along the anteroposterior axis. We demonstrate here that although the anteroposterior levels of r2 to r6 express Hox genes they do not have inducing activity on more anterior territories. If transposed at the posterior rhombencephalon and trunk level, however, the same anterior regions are able to express Hox gene such as Hoxa-2, a-3 or b-4. We also provide evidence that these signals are transferred by two paths: one vertical, arising from the paraxial mesoderm, and one planar, travelling in the neural epithelium. The competence to express Hox genes extends up to the forebrain and midbrain but expression of Hox genes does not preclude Otx2 expression in these territories and results only in slight changes in their phenotypes. Similarly, rhombomeres transplanted to posterior truncal levels turned out to be able to express posterior genes of the first eight paralog groups to the exclusion of others located downstream in the Hox genes genomic clusters. This suggests that the neural tube is divided into large territories characterized by different Hox gene regulatory features.

Hoxa-2 expression in normal and transposed rhombomeres: independent regulation in the neural tube and neural crest

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 911-923 ◽  
Author(s):  
V. Prince ◽  
A. Lumsden
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Cell Population ◽  
Neural Tube ◽  
Hox Genes ◽  
Expression Patterns ◽  
Branchial Arch ◽  
Gene Expression Patterns ◽  
Hox Gene ◽  
Crest Cell

In this study we have cloned the chick Hoxa-2 gene and analysed its expression during early development. We find that Hoxa-2 has a rostral limit of expression in the rhombencephalic neural tube corresponding precisely to the boundary between rhombomeres (r)1 and 2; a limit further rostral than any other Hox gene reported to date. Neural crest migrates from r2 to populate the first branchial arch, yet although Hoxa-2 is expressed down the full dorsoventral extent of r2 during the phase of neural crest emigration, there is no Hoxa-2 expression in either the emergent neural crest or in the first branchial arch. Conversely, at the level of r4, both the neural tube and the neural crest cells, which migrate out of this rhombomere to populate the second branchial arch, express Hoxa-2. Other Hox genes expressed in the rhombencephalic neural tube demonstrate a transfer of expression from neural tube to neural crest at all axial levels of expression. Hoxa-2 is thus unusual in demonstrating separate anterior expression limits in neural tube and neural crest; this allowed us to test whether Hox gene expression patterns in neural crest are determined by migratory pathways or are prespecified by the site of origin in the neuroepithelium. Grafting experiments in which pairs of rhombomeres were transplanted to ectopic sites at the time of rhombomere boundary formation reveal a prepatterning of the neural crest with respect to Hoxa-2 expression. The decision to down-regulate Hoxa-2 expression in r2-derived neural crest, but to maintain Hoxa-2 expression in r4-derived neural crest is intrinsic to the premigratory crest cell population. Thus, following grafting of r4 to the r2 site and vice-versa, Hoxa-2 expression is maintained in r4-derived neural crest, but lost in r2-derived neural crest.

Analysis of Hox gene expression in the chick limb bud

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1449-1466 ◽  
Author(s):  
C.E. Nelson ◽  
B.A. Morgan ◽  
A.C. Burke ◽  
E. Laufer ◽  
E. DiMambro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Hind Limb ◽  
Hox Genes ◽  
Expression Patterns ◽  
Limb Bud ◽  
Posterior Portion ◽  
Hox Gene ◽  
Hoxd Gene

The vertebrate Hox genes have been shown to be important for patterning the primary and secondary axes of the developing vertebrate embryo. The function of these genes along the primary axis of the embryo has been generally interpreted in the context of positional specification and homeotic transformation of axial structures. The way in which these genes are expressed and function during the development of the secondary axes, particularly the limb, is less clear. In order to provide a reference for understanding the role of the Hox genes in limb patterning, we isolated clones of 23 Hox genes expressed during limb development, characterized their expression patterns and analyzed their regulation by the signalling centers which pattern the limb. The expression patterns of the Abd-B-related Hoxa and Hoxd genes have previously been partially characterized; however, our study reveals that these genes are expressed in patterns more dynamic and complex than generally appreciated, only transiently approximating simple, concentric, nested domains. Detailed analysis of these patterns suggests that the expression of each of the Hoxa and Hoxd genes is regulated in up to three independent phases. Each of these phases appears to be associated with the specification and patterning of one of the proximodistal segments of the limb (upper arm, lower arm and hand). Interestingly, in the last of these phases, the expression of the Hoxd genes violates the general rule of spatial and temporal colinearity of Hox gene expression with gene order along the chromosome. In contrast to the Abd-B-related Hoxa and Hoxd genes, which are expressed in both the fore and hind limbs, different sets of Hoxc genes are expressed in the two limbs. There is a correlation between the relative position of these genes along the chromosome and the axial level of the limb bud in which they are expressed. The more 3′ genes are expressed in the fore limb bud while the 5′ genes are expressed in the hind limb bud; intermediate genes are transcribed in both limbs. However, there is no clear correlation between the relative position of the genes along the chromosome and their expression domains within the limb. With the exception of Hoxc-11, which is transcribed in a posterior portion of the hind limb, Hoxc gene expression is restricted to the anterior/proximal portion of the limb bud. Importantly, comparison of the distributions of Hoxc-6 RNA and protein products reveals posttranscriptional regulation of this gene, suggesting that caution must be exercised in interpreting the functional significance of the RNA distribution of any of the vertebrate Hox genes. To understand the genesis of the complex patterns of Hox gene expression in the limb bud, we examined the propagation of Hox gene expression relative to cell proliferation. We find that shifts in Hox gene expression cannot be attributed to passive expansion due to cell proliferation. Rather, phase-specific Hox gene expression patterns appear to result from a context-dependent response of the limb mesoderm to Sonic hedgehog. Sonic hedgehog (the patterning signal from the Zone of Polarizing Activity) is known to be able to activate Hoxd gene expression in the limb. Although we find that Sonic hedgehog is capable of initiating and polarizing Hoxd gene expression during both of the latter two phases of Hox gene expression, the specific patterns induced are not determined by the signal, but depend upon the temporal context of the mesoderm receiving the signal. Misexpression of Sonic hedgehog also reveals that Hoxb-9, which is normally excluded from the posterior mesenchyme of the leg, is negatively regulated by Sonic hedgehog and that Hoxc-11, which is expressed in the posterior portion of the leg, is not affected by Sonic hedgehog and hence is not required to pattern the skeletal elements of the lower leg.

scholarly journals The Role of Histone Demethylases and DNA Methyltransferases in the Transcription Regulation of HOX Genes in PML-RARa+ AML Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3921-3921
Author(s):  
Katerina Rejlova ◽  
Alena Musilova ◽  
Martina Slamova ◽  
Karel Fiser ◽  
Karolina Skvarova Kramarzova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Fold Increase ◽  
Dna Methyltransferases ◽  
Histone Mark ◽  
Gene Promoters ◽  
Histone Demethylases ◽  
Atra Treatment ◽  
Hox Gene

Abstract Homeobox genes (HOX) encode transcription factors that are frequently deregulated in leukemias. Our previous results showed that HOX gene expression differs among genetically characterized subtypes of pediatric acute myeloid leukemia (AML). Specifically, PML-RARa positive AML patients have overall lowest HOX gene expression which positively correlates with expression of histone 3 lysine 27 (H3K27) demethylases - JMJD3 and UTX and negatively with the expression of DNA methyltransferases - DNMT3a and DNMT3b. Interestingly, JMJD3 was already shown to be a direct target of PML-RARa protein (Martens, JH et al, 2010, Cancer Cell). From these findings we postulated a hypothesis that reduced levels of HOX genes in PML-RARa positive AML are a consequence of suppressed expression of histone demethylases resulting in increased H3K27 methylation and/or of elevated levels of DNMTs leading to de novoDNA methylation. We studied the role of histone demethylases and DNMTs in the regulation of HOX gene expression and the effect of treatment in PML-RARa positive cell lines (NB4 and ATRA-resistant clones NB4-LR2 and NB4-MR2). We treated NB4 cell line by all-trans retinoic acid (ATRA; 1uM), which was described to release the differentiation block caused by the presence of PML-RARa and to degrade the fusion protein. We observed that expression of particular HOX genes (HOXA1, HOXA3, HOXA4, HOXA5, HOXA7, HOXB4, HOXB6) measured by qPCR was significantly increased after ATRA treatment. While the level of JMJD3 was significantly increased upon ATRA treatment as well, the expression of UTX did not change. Furthermore, we detected significantly reduced expression of DNMT3b gene. To exclude a non-specific effect of ATRA, independent of PML-RARa, we used resistant clones LR2 and MR2 bearing mutations in retinoic acid-binding domain. HOX gene expression together with JMJD3, UTX and DNMT3b expression did not change upon ATRA treatment. These results confirm the PML-RARa-dependent regulation of HOX genes. To test the role of JMJD3 in the HOX gene expression regulation, we cultured NB4 cells with a specific inhibitor of histone demethylases, GSK-J4 (1 uM, 10 uM), in the presence of ATRA. The co-treatment caused significant decrease in the expression of studied HOX genes (HOXA1, HOXA3, HOXA5, HOXA7, HOXA10, HOXB4, HOXB6) in comparison to ATRA alone which supports the role of JMJD3 in the transcription regulation. Further, we performed chromatin immunoprecipitation (ChIP) to investigate if the changes of HOX gene expression upon ATRA and GSK-J4 treatment would correspond with changes of histone code on HOX gene promoter regions. ATRA treatment caused reduction of repressive histone mark (H3K27me3) on particular HOX gene promoters (HOXA1, HOXA3, HOXA5, HOXA7), by contrast, combinational treatment of ATRA and GSK-J4 reversed this effect. Accordingly, we detected that ATRA/GSK-J4 co-treatment reduced active histone mark H3K4me2. Next we were interested if JMJD3 inhibition would interfere with the differentiation effect of ATRA. As shown previously, ATRA treatment alone caused differentiation of NB4 cell line whereas the combination with GSK-J4 did not reduce the effect. Interestingly, in addition to differentiation it led cells to apoptosis. Combination of drugs (ATRA - 1uM, GSK-J4 - 1, 2, 5uM) increased significantly the percentage of dead cells in comparison to ATRA or GSK treatment alone (GSK-J4 alone vs in combination with ATRA, 1uM - 1.8 fold, 2uM - 2.2 fold, 5 uM - 2.3 fold increase). Next we measured apoptosis in resistant clones LR2 and MR2. In both cases the highest concentration used of GSK-J4 (5uM) in combination with ATRA caused significant increase of dead cells as well (LR2 - 2.1 fold, MR2 - 2.0 fold increase). Our results indicate that JMJD3 is responsible for the regulation of HOX gene expression in PML-RARa positive leukemia since changes of HOX gene expression correspond with histone modifications on the regions of HOX gene promoters. We assume that DNA methylation driven by DNMT3b can also participate in this process. Moreover, our findings demonstrate potential therapeutic implications of GSK-J4 inhibitor in combination with ATRA in patients with acute promyelocytic leukemia who are not responsive to ATRA monotherapy. Supported by P304/12/2214 and GAUK 196616 Disclosures No relevant conflicts of interest to declare.

A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 37-49 ◽  
Author(s):  
J.N. Maloof ◽  
J. Whangbo ◽  
J.M. Harris ◽  
G.D. Jongeward ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Hox Genes ◽  
Wnt Signaling Pathway ◽  
Beta Catenin ◽  
Hox Gene ◽  
C Elegans ◽  
Neuroblast Migration ◽  
Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes the anterior limit of Hox gene expression

Development ◽  
2000 ◽  
Vol 127 (1) ◽  
pp. 177-186 ◽  
Author(s):  
C. Irving ◽  
I. Mason
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Protein A ◽  
Anterior Segment ◽  
Morphogen Gradient ◽  
Current Evidence ◽  
Hox Gene ◽  
Developmental Fate ◽  
Developmental Patterning

Current evidence suggests that the anterior segment of the vertebrate hindbrain, rhombomere 1, gives rise to the entire cerebellum. It is situated where two distinct developmental patterning mechanisms converge: graded signalling from an organising centre (the isthmus) located at the midbrain/hindbrain boundary confronts segmentation of the hindbrain. The unique developmental fate of rhombomere 1 is reflected by it being the only hindbrain segment in which no Hox genes are expressed. In this study we show that ectopic FGF8 protein, a candidate for the isthmic organising activity, is able to induce and repress gene expression within the hindbrain in a manner appropriate to rhombomere 1. Using a heterotopic, heterospecific grafting strategy we demonstrate that rhombomere 1 is able to express Hox genes but that both isthmic tissue and FGF8 inhibit their expression. Inhibition of FGF8 function in vivo shows that it is responsible for defining the anterior limit of Hox gene expression within the developing brain and thereby specifies the extent of the rl territory. Previous studies have suggested that a retinoid morphogen gradient determines the axial limit of expression of individual Hox genes within the hindbrain. We propose a model whereby activation by retinoids is antagonised by inhibition by FGF8 in the anterior hindbrain to set aside the territory from which the cerebellum will develop.

scholarly journals Posterior Hox Gene Expression and Differential Androgen Regulation in the Developing and Adult Rat Prostate Lobes

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1235-1245 ◽  
Author(s):  
Liwei Huang ◽  
Yongbing Pu ◽  
David Hepps ◽  
David Danielpour ◽  
Gail S. Prins
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Prostate Gland ◽  
Hox Gene ◽  
Expression Levels ◽  
Adult Rat ◽  
Organ Specific ◽  
Androgen Regulation ◽  
Hox Code ◽  
Rat Prostate

Axis positioning and tissue determination during development involve coordinated expression of Hox genes throughout the body. The most posterior Hox gene clusters are involved in prostate organogenesis. In the present study, we characterized and compared the expression profiles of posterior (5′) Hox genes in the separate lobes of the adult rat prostate gland, the coagulating gland, seminal vesicles, and epididymis using quantitative real-time RT-PCR. These genes include Hoxa9–11, Hoxa13, Hoxd13, and Hoxb13. We identified a unique Hox code for each of these organs and propose that this contributes to the organ-specific and prostate lobe-specific identities in the adult rat. Using the ventral prostate (VP) as a model, we characterized the Hox genes expression patterns over time from birth through adulthood. Expression levels of the three Hox13 genes and Hoxa10 were significantly higher in the adult VP compared with the neonatal developing VP suggesting an important role during adult homeostasis. In contrast, Hoxa9 and Hoxa11 levels declined after morphogenesis suggesting a specific developmental role. Overall, the Hoxb13 gene exhibited the most striking temporal and organ-specific differences. Using in situ hybridization and immunohistochemistry, a distinct Hoxb13 anterior-to-posterior expression gradient was observed with the highest expression levels in the VP luminal epithelial cells, moderate levels in the lateral prostate, and low expression in the dorsal prostate. An expression gradient was also observed along the ductal length in all three prostate lobes with strongest expression at the distal tips and limited expression in the proximal ducts. After infection with a lentivirus expressing the Hoxb13 gene, NRP-152 cells cultured under nondifferentiating conditions exhibited robust cytokeratin 8 immunostain indicating that Hoxb13 expression drives luminal cell differentiation in the rat epithelium. Androgen regulation of prostatic Hox gene expression was examined during development in vitro and after castration in the adult rat. In the neonatal VP, all six Hox genes were significantly up-regulated by androgens, whereas none of the genes were affected by testosterone in the lateral prostate. In the adult rat, castration resulted in up-regulation of Hoxa9 and Hoxa13 in the VP and down-regulation of Hoxb13 in the dorsal prostate and lateral prostate. Taken together, we conclude that the prostatic Hox genes reach a destined expression level at specific developmental time points in the prostate gland and possess differential androgenic regulation in a temporal and lobe-specific manner. We suggest that this timely Hox code participates in determining lobe-specific prostatic identity and cellular differentiation.

scholarly journals Dorsoventral decoupling of Hox gene expression underpins the diversification of molluscs

2019 ◽  
Vol 117 (1) ◽  
pp. 503-512 ◽  
Author(s):  
Pin Huan ◽  
Qian Wang ◽  
Sujian Tan ◽  
Baozhong Liu
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Expression Patterns ◽  
Dorsal Side ◽  
The Other ◽  
Strongly Correlated ◽  
Expression Data ◽  
Shell Formation ◽  
Hox Gene ◽  
Evolutionary Diversification

In contrast to the Hox genes in arthropods and vertebrates, those in molluscs show diverse expression patterns with differences reported among lineages. Here, we investigate 2 phylogenetically distant molluscs, a gastropod and a polyplacophoran, and show that the Hox expression in both species can be divided into 2 categories. The Hox expression in the ventral ectoderm generally shows a canonical staggered pattern comparable to the patterns of other bilaterians and likely contributes to ventral patterning, such as neurogenesis. The other category of Hox expression on the dorsal side is strongly correlated with shell formation and exhibits lineage-specific characteristics in each class of mollusc. This generalized model of decoupled dorsoventral Hox expression is compatible with known Hox expression data from other molluscan lineages and may represent a key characteristic of molluscan Hox expression. These results support the concept of widespread staggered Hox expression in Mollusca and reveal aspects that may be related to the evolutionary diversification of molluscs. We propose that dorsoventral decoupling of Hox expression allowed lineage-specific dorsal and ventral patterning, which may have facilitated the evolution of diverse body plans in different molluscan lineages.

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