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At least 19 recordsLinked to original sources

PubMed1999

Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.

To explore the possibility that deregulated HOX gene expression might commonly occur during leukemic hematopoiesis, we compared the relative levels of expression of these and related genes in phenotypically and functionally defined subpopulations of AML blasts and normal hematopoietic cells. Initially, a semi-quantitative RT-PCR technique was used to amplify total cDNA from total leukemic blast cell populations from 20 AML patients and light density cells from four normal bone marrows. Expression of HOX genes (A9, A10, B3 and B4), MEIS1 and MLL was easily detected in the majority of AML samples with the exception of two samples from patients with AML subtype M3 (which expressed only MLL). Low levels of HOXA9 and A10 but not B3 or B4 were seen in normal marrow while MLL was easily detected. PBX1a was difficult to detect in any AML sample but was seen in three of four normal marrows. Cells from nine AML patients and five normal bone marrows were FACS-sorted into CD34+CD38-, CD34+CD38+ and CD34-subpopulations, analyzed for their functional properties in long-term culture (LTC) and colony assays, and for gene expression using RT-PCR. 93 +/- 14% of AML LTC-initiating cells, 92 +/- 14% AML colony-forming cells, and >99% of normal LTC-IC and CFC were CD34+. The relative level of expression of the four HOX genes in amplified cDNA from CD34- as compared to CD34+CD38- normal cells was reduced >10-fold. However, in AML samples this down-regulation in HOX expression in CD34- as compared to CD34+CD38- cells was not seen (P < 0.05 for comparison between AML and normal). A similar difference between normal and AML subpopulations was seen when the relative levels of expression of MEIS1, and to a lesser extent MLL, were compared in CD34+ and CD34- cells (P < 0.05). In contrast, while some evidence of down-regulation of PBX1a was found in comparing CD34- to CD34+ normal cells it was difficult to detect expression of this gene in any subpopulation from most AML samples. Thus, the down-regulation of HOX, MEIS1 and to some extent MLL which occurs with normal hematopoietic differentiation is not seen in AML cells with similar functional and phenotypic properties.

ADP-ribosyl Cyclase↗

PubMedDate not supplied

Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria.

Amino Acid Sequence↗

PubMed2006

Endocrine regulation of HOX genes.

Hox genes have a well-characterized role in embryonic development, where they determine identity along the anteroposterior body axis. Hox genes are expressed not only during embryogenesis but also in the adult, where they are necessary for functional differentiation. Despite the known function of these genes as transcription factors, few regulatory mechanisms that drive Hox expression are known. Recently, several hormones and their cognate receptors have been shown to regulate Hox gene expression and thereby mediate development in the embryo as well as functional differentiation in the adult organism. Estradiol, progesterone, testosterone, retinoic acid, and vitamin D have been shown to regulate Hox gene expression. In the embryo, the endocrine system directs axial Hox gene expression; aberrant Hox gene expression due to exposure to endocrine disruptors contributes to the teratogenicity of these compounds. In the adult, endocrine regulation of Hox genes is necessary to enable such diverse functions as hematopoiesis and reproduction; endocrinopathies can result in dysregulated HOX gene expression affecting physiology. By regulating HOX genes, hormonal signals utilize a conserved mechanism that allows generation of structural and functional diversity in both developing and adult tissues. This review discusses endocrine Hox regulation and its impact on physiology and human pathology.

Animals↗

PubMed2000

Implantation in the human: the role of HOX genes.

HOX genes are transcription factors that are essential for the proper development of the müllerian tract in the embryonic period. It has been discovered that HOX genes are expressed in the adult uterus. Two of them, Hoxa10 and Hoxa11, have been demonstrated to be necessary for uterine receptivity and implantation in mice. Recent evidence also suggests such a role for HOX genes in humans. They are likely to be essential regulators of endometrial development in preparation for implantation. This article reviews the role of the HOX genes in the reproductive tract, their patterns of expression and regulation, the outcome of deficient HOX gene expression, and their potential mechanisms of action. The process of implantation is complex, and many molecular markers have been found expressed at high levels in the endometrium in the peri-implantation window. Targeted disruption has revealed that most of these molecules are redundant and not essential for implantation. The importance of Hox genes in this process has been well documented, and they remain one of the few well-characterized molecules necessary for implantation.

Animals↗

PubMed2004

Molecular regulation of mullerian development by Hox genes.

HOX genes are a family of regulatory molecules that encode conserved transcription factors controlling aspects of morphogenesis and cell differentiation during normal embryonic development. All metazoans possess a common genetic system for embryonic patterning, and this system is also used in the reproductive tract. Hox genes are also expressed in the adult uterus. Hox genes are essential both for the development of mullerian tract in the embryonic period and adult function. Sex steroids regulate Hox gene expression during embryonic and endometrial development in the menstrual cycle. EMX2 and beta(3)-integrin acting downstream of Hoxa10 gene are likely involved in both these developmental processes. This article reviews the role and molecular regulation of Hox genes in reproductive tract development.

Animals↗

PubMed2000

Caenorhabditis elegans embryonic axial patterning requires two recently discovered posterior-group Hox genes.

Hox genes encode highly conserved transcription factors that control regional identities of cells and tissues along the developing anterior-posterior axis, probably in all bilaterian metazoans. However, in invertebrate embryos other than Drosophila, Hox gene functions remain largely unknown except by inference from sequence similarities and expression patterns. Recent genomic sequencing has shown that Caenorhabditis elegans has three Hox genes of the posterior paralog group [Ruvkun, G. & Hobert, O. (1998) Science 282, 2033-2041]. However, only one has been previously identified genetically, and it is not required for embryonic development [Chisholm, A. (1991) Development (Cambridge, U.K.) 111, 921-932]. Herein, we report identification of the remaining two posterior paralogs as the nob-1 gene and the neighboring php-3 gene. Elimination of nob-1 and php-3 functions causes gross embryonic defects in both posterior patterning and morphogenetic movements of the posterior hypodermis, as well as posterior-to-anterior cell fate transformations and lethality. The only other Hox gene essential for embryogenesis is the labial/Hox1 homolog ceh-13, required for more anterior patterning [Brunschwig, K., Wittmann, C., Schnabel, R., Burglin, T. R., Tobler, H. & Muller, F. (1999) Development (Cambridge, U.K.) 126, 1537-1546]. Therefore, essential embryonic patterning in C. elegans requires only Hox genes of the anterior and posterior paralog groups, raising interesting questions about evolution of the medial-group genes.

Amino Acid Sequence↗

PubMed2002

Limb malformations and the human HOX genes.

HOX genes encode a family of transcription factors of fundamental importance for body patterning during embryonic development. Humans, like most vertebrates, have 39 HOX genes organized into four clusters, with major roles in the development of the central nervous system, axial skeleton, gastrointestinal and urogenital tracts, external genitalia, and limbs. The first two limb malformations shown to be caused by mutations in the human HOX genes were synpolydactyly and hand-foot-genital syndrome, which result from mutations in HOXD13 and HOXA13, respectively. This review describes a variety of limb malformations now known to be caused by specific different mutations in these two genes, including polyalanine tract expansions, nonsense mutations, and missense mutations, many with phenotypic consequences that could not have been predicted from previous knowledge of mouse models or HOX protein function. Limb malformations may also result from chromosomal deletions involving the HOXD and HOXA clusters, and from regulatory mutations affecting single or multiple HOX genes.

Animals↗

PubMed1999

Specification of distinct motor neuron identities by the singular activities of individual Hox genes.

Hox genes have been implicated in specifying positional values along the anteroposterior axis of the caudal central nervous system, but their nested and overlapping expression has complicated the understanding of how they confer specific neural identity. We have employed a direct gain-of-function approach using retroviral vectors to misexpress Hoxa2 and Hoxb1 outside of the normal Hox expression domains, thereby avoiding complications resulting from possible interactions with endogenous Hox genes. Misexpression of either Hoxa2 or Hoxb1 in the anteriormost hindbrain (rhombomere1, r1) leads to the generation of motor neurons in this territory, even though it is normally devoid of this cell type. These ectopic neurons have the specific identity of branchiomotor neurons and, in the case of Hoxb1-induced cells, their axons leave the hindbrain either by fasciculating with the resident cranial motor axons at isthmic (trochlear) or r2 (trigeminal) levels of the axis or via novel ectopic exit points in r1. Next, we have attempted to identify the precise branchiomotor subtypes that are generated after misexpression and our results suggest that the ectopic motor neurons generated following Hoxa2 misexpression are trigeminal-like, while those generated following Hoxb1 misexpression are facial-like. Our data demonstrate, therefore, that at least to a certain extent and for certain cell types, the singular activities of individual Hox genes (compared to a combinatorial mode of action, for example) are sufficient to impose on neuronal precursor cells the competence to generate distinctly specified cell types. Moreover, as these particular motor neuron subtypes are normally generated in the most anterior domains of Hoxa2 and Hoxb1 expression, respectively, our data support the idea that the main site of individual Hox gene action is in the anteriormost subdomain of their expression, consistent with the phenomenon of posterior dominance.

Animals↗

PubMed2003

Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes.

Hox genes are instrumental in assigning segmental identity in the developing hindbrain. Auto-, cross- and para-regulatory interactions help establish and maintain their expression. To understand to what extent such regulatory interactions shape neuronal patterning in the hindbrain, we analysed neurogenesis, neuronal differentiation and motoneuron migration in Hoxa1, Hoxb1 and Hoxb2 mutant mice. This comparison revealed that neurogenesis and differentiation of specific neuronal subpopulations in r4 was impaired in a similar fashion in all three mutants, but with different degrees of severity. In the Hoxb1 mutants, neurons derived from the presumptive r4 territory were re-specified towards an r2-like identity. Motoneurons derived from that territory resembled trigeminal motoneurons in both their migration patterns and the expression of molecular markers. Both migrating motoneurons and the resident territory underwent changes consistent with a switch from an r4 to r2 identity. Abnormally migrating motoneurons initially formed ectopic nuclei that were subsequently cleared. Their survival could be prolonged through the introduction of a block in the apoptotic pathway. The Hoxa1 mutant phenotype is consistent with a partial misspecification of the presumptive r4 territory that results from partial Hoxb1 activation. The Hoxb2 mutant phenotype is a hypomorph of the Hoxb1 mutant phenotype, consistent with the overlapping roles of these genes in facial motoneuron specification. Therefore, we have delineated the functional requirements in hindbrain neuronal patterning that follow the establishment of the genetic regulatory hierarchy between Hoxa1, Hoxb1 and Hoxb2.

Animals↗

PubMed2001

Current problems with the zootype and the early evolution of Hox genes.

"Hox cluster type" genes have sparked intriguing attempts to unite all metazoan animals by a shared pattern of expression and genomic organization of a specific set of regulatory genes. The basic idea, the zootype concept, claims the conservation of a specific set of "Hox cluster type genes" in all metazoan animals, i.e., in the basal diploblasts as well as in the derived triploblastic animals. Depending on the data used and the type of analysis performed, different opposing views have been taken on this idea. We review here the sum of data currently available in a total evidence analysis, which includes morphological and the most recent molecular data. This analysis highlights several problems with the idea of a simple "Hox cluster type" synapomorphy between the diploblastic and triploblastic animals and suggests that the "zootype differentiation" of the Hox cluster most likely is an invention of the triploblasts. The view presented is compatible with the idea that early Hox gene evolution started with a single proto-Hox (possibly a paraHox) gene. J. Exp. Zool. (Mol. Dev. Evol.) 291:169-174, 2001.

Animals↗

PubMedDate not supplied

HOX genes in human cancers.

Knowledge about transcription factors is crucial for understanding the molecular basis of neoplasia. Homeobox-containing genes are a family of transcription factors mostly involved in normal development. Class I human homeobox-containing genes (HOX genes) are organized in four clusters on different chromosomes. The order of the genes within each cluster is highly conserved throughout evolution suggesting that the physical organization of HOX genes may be (1) essential for their expression and (2) responsible for major biological functions. We have studied HOX gene expression in several human tissues and organs as well as in their neoplastic counterparts. We have observed (a) characteristic patterns of HOX gene expression for each normal solid organ analyzed, (b) altered HOX gene expression in kidney and colon cancer, (c) a correlation between HOX gene expression and different histological types of primary small cell lung cancer (SCLC) and (d) marked alterations of HOX gene expression among primary and metastatic SCLC variant types. Furthermore, we have shown that differential patterns of HOX gene expression correlate with the adhesion profile (VLA-2, VLA-5, VLA-6 and ICAM-1) and N-RAS mutation in clonal melanoma populations isolated from a single human melanoma metastasis. This suggests that HOX genes act as a network of transcriptional regulators involved in the process of cell to cell communication during normal morphogenesis, the alteration of which may contribute to the evolution of cancer.

Adult↗

PubMed1994

HOX gene expression in human small-cell lung cancers xenografted into nude mice.

Transcription factors are crucial to an understanding of the molecular basis of neoplasia. Homeobox-containing genes are a family of transcriptional regulators encoding DNA-binding homeodomains, involved in the control of normal development. Class-I human homeobox-containing genes (HOX genes) display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox-genes has been associated with both morphological abnormalities and oncogenesis. We have recently observed that alterations in HOX gene expression are detectable in kidney and colon cancer when compared to the corresponding normal organs. Here we have analyzed the expression of HOX genes in primary and metastatic human small-cell lung cancer (SCLC) xenografted in nude mice, in order to investigate whether HOX gene expression correlates with the histology and stage of SCLC progression. The results show that different SCLCs display differential patterns of HOX gene expression. Furthermore, in SCLC, the number of actively expressed HOX genes might be substantially lower in metastatic cancers than in primary tumors. The alteration in HOX gene expression in SCLCs mainly concerns the HOX B and C loci. This finding suggests that downregulation of HOX genes may play a role in small-cell lung cancer progression, possibly through their implication in tumor suppression.

Animals↗

PubMed2005

Phylogeny of the insect homeobox gene (hox) cluster.

The homeobox (Hox) genes form an evolutionarily conserved family encoding transcription factors that play major roles in segmental identity and organ specification across species. The canonical grouping of Hox genes present in the HOM-C cluster of Drosophila or related clusters in other organisms includes eight "typical" genes, which are localized in the order labial (lab), proboscipedia (pb), Deformed (Dfd), Sex combs reduced (Scr), Antennapedia (Antp), Ultrabithorax (Ubx), abdominalA (abdA), and AbdominalB (AbdB). The members of Hox cluster are expressed in a distinct anterior to posterior order in the embryo. Analysis of the relatedness of different members of the Hox gene cluster to each other in four evolutionarily diverse insect taxa revealed that the loci pb/Dfd and AbdB, which are farthest apart in linkage, had a high degree of evolutionary relatedness, indicating that pb/Dfd type anterior genes and AbdB are closest to the ancestral anterior and posterior Hox genes, respectively. The greater relatedness of other posterior genes Ubx and abdA to the more anterior genes such as Antp and Scr suggested that they arose by gene duplications in the more anterior members rather than the posterior AbdB.

Animals↗

PubMed1999

egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function.

Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes are expressed in sequential overlapping domains where they control the ability of each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities of Hox proteins are sex-specific in this tissue, resulting in sex-specific patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused, whereas in males, alternating domains of syncytial and unfused cells develop. We have found that the gene egl-27, which encodes a C. elegans homologue of a chromatin regulatory factor, specifies these patterns by regulating both Hox gene expression and Hox protein function. In egl-27 mutants, the expression domains of Hox genes in these cells are shifted posteriorly, suggesting that egl-27 influences A/P positional information. In addition, egl-27 controls Hox protein function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5 activity, whereas in males it permits a combinatorial interaction between LIN-39 and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27 elaborates a simple Hox expression pattern into complex patterns of cell fates. Taken together, these results implicate egl-27 in the diversification of cell fates along the A/P axis and suggest that chromatin reorganization is necessary for controlling Hox gene expression and Hox protein function.

Animals↗

PubMed1998

Region-specific expression of murine Hox genes implies the Hox code-mediated patterning of the digestive tract.

BACKGROUND: Hox genes encode transcription factors which are involved in the establishment of regional identities along the anteroposterior (AP) body axis. To elucidate the AP patterning of the digestive tract, we have systematically examined the expression patterns of Hox genes belonging to paralogue groups 6, 7, 8 and 9 by whole-mount in situ hybridization and by section in situ hybridization analyses. RESULTS: The expression patterns of these genes showed co-linearity along the wall of the digestive tract, thereby yielding the Hox code of the gut. The expression boundaries of the Hox genes at later stages (12.5 d.p.c.) corresponded to the morphological boundaries of individual gut subdomains. CONCLUSIONS: The visceral mesoderm-restricted expression suggested that the Hox code primarily functions in the mesenchymal specification which eventually leads to the regional differentiation of gut subdomains as the result of epithelial-mesenchymal interactions. Overlapping expression patterns were found among the paralogous Hox genes, indicating that the paralogues may have redundant functions in the specification of the gut.

Animals↗

PubMed1995

Gain of function mutations for paralogous Hox genes: implications for the evolution of Hox gene function.

To investigate the functions of paralogous Hox genes, we compared the phenotypic consequences of altering the embryonic patterns of expression of Hoxb-8 and Hoxc-8 in transgenic mice. A comparison of the phenotypic consequences of altered expression of the two paralogs in the axial skeletons of newborns revealed an array of common transformations as well as morphological changes unique to each gene. Divergence of function of the two paralogs was clearly evident in costal derivatives, where increased expression of the two genes affected opposite ends of the ribs. Many of the morphological consequences of expanding the mesodermal domain and magnitude of expression of either gene were atavistic, inducing the transformation of axial skeletal structures from a modern to an earlier evolutionary form. We propose that regional specialization of the vertebral column has been driven by regionalization of Hox gene function and that a major aspect of this evolutionary progression may have been restriction of Hox gene expression.

Animals↗

PubMed1990

Mouse Hox-3.4: homeobox sequence and embryonic expression patterns compared with other members of the Hox gene network.

A putative mouse homeobox gene (Hox-3.4) was previously identified 4kb downstream of the Hox-3.3 (Hox-6.1)* gene (Sharpe et al. 1988). We have now sequenced the Hox-3.4 homeobox region. The predicted amino acid sequence shows highest degree of homology in the mouse with Hox-1.3 and -2.1. This, together with similarities in the genomic organisation around these three genes, suggests that they are comembers of a subfamily, derived from a common ancestor. Hox-3.4 appears to be a homologue of the Xenopus Xlhbox5 and human cp11 genes (Fritz and De Robertis, 1988; Simeone et al. 1988). Using a panel of mouse-hamster somatic cell hybrids we have mapped the Hox-3.4 gene to chromosome 15. From the results of in situ hybridization experiments, we describe the distribution of Hox-3.4 transcripts within the 12 1/2 day mouse embryo, and we compare this with the distributions of transcripts shown by seven other members of the Hox gene network. We note three consistencies that underlie the patterns of expression shown by Hox-3.4. First, the anterior limits of Hox-3.4 transcripts in the embryo are related to the position of the Hox-3.4 gene within the Hox-3 locus. Second, the anterior limits of Hox-3.4 expression within the central nervous system are similar to those shown by subfamily homologues Hox-2.1 and Hox-1.3, although the tissue-specific patterns of expression for these three genes show many differences. Third, the patterns of Hox-3.4 expression within the spinal cord and the testis are very similar to those shown by a neighbouring Hox-3 gene (Hox-3.3), but they are quite different from those shown by Hox-1 genes (Hox-1.2, -1.3 and -1.4).

Amino Acid Sequence↗

PubMed1989

Anterior boundaries of Hox gene expression in mesoderm-derived structures correlate with the linear gene order along the chromosome.

The developmental expression patterns of four genes, Hox 1.1, Hox 1.2, Hox 1.3 and Hox 3.1, were examined by in situ hybridization to serial embryonic sections. The three genes of the Hox 1 cluster, used in this study, map to adjacent positions along chromosome 6, whereas the Hox 3.1 gene maps to the Hox 3 cluster on chromosome 15. The anterior expression limits in segmented mesoderm varied among the four genes examined. Interestingly, a linear correlation exists between the position of the gene along the chromosome and the extent of anterior expression. Genes that are expressed more posterior are also more restricted in their expression in other mesoderm-derived tissues. The order of expression anterior to posterior was determined as: Hox 1.3, Hox 1.2, Hox 1.1 and Hox 3.1. Similarly, genes of the Drosophila Antennapedia and Bithorax complex specifying segment identity also exhibit anterior expression boundaries that correlate with gene position. The data suggest that Hox genes may specify positional information along the anterior-posterior axis during the formation of the body plan.

Animals↗