Role Of Homeobox Genes Research Articles

An insight into the diagnostic and prognostic value of HOX A13's expression in non-muscle invasive bladder cancer.

BackgroundSeveral studies have interrogated the molecular pathways and their interacting genes underlying bladder cancer (BCa) tumorigenesis, yet, the role of homeobox genes is still poorly understood. Specifically, HOXA13, which plays an important role as a major actor in the urogenital tract's development.MethodsImmunohistochemical (IHC) staining was performed to inspect the differential expression of HOXA13 protein in non‐muscle‐invasive bladder cancer (NMIBC) and non‐tumoral tissues. A semiquantitative scoring system was adopted to evaluate the IHC labeling. Correlation to clinical parameters was performed by descriptive statistics. Overall survival was estimated by the Kaplan–Meier method and Cox regression model. The functional HOX A13 protein association networks (PPI) were obtained using String 11.0 database.ResultsHOX A13 exhibited cytoplasmic and nuclear staining. Its expression levels were lower in high‐grade NMIBC (HG NMIBC) compared to low‐grade ones (LG NMIBC). The expression of HOX A13 was correlated to tumor grade (LG/HG) (p = 0.036) and stage (TA/T1) (p = 0.036). Nevertheless, its expression was not correlated to clinical parameters and was not able to predict the overall survival of patients with HG NMIBC. Finally, PPI analysis revealed that HOX A13 seems to be a part of a molecular network holding mainly PBX1, MEIS, ALDH1A2, HOX A10, and HOX A11.ConclusionThe deregulation of HOX A13 is not associated with the prognosis of BCa. It seems to be rather implicated in the early initiation of urothelial tumorigenesis and thus may serve as a diagnostic marker in patients with NMIBC. Further experimentations on larger validation sets are mandatory.

Homeobox Genes in Cancers: From Carcinogenesis to Recent Therapeutic Intervention.

The homeobox (HOX) genes encoding an evolutionarily highly conserved family of homeodomain-containing transcriptional factors are essential for embryogenesis and tumorigenesis. HOX genes are involved in cell identity determination during early embryonic development and postnatal processes. The deregulation of HOX genes is closely associated with numerous human malignancies, highlighting the indispensable involvement in mortal cancer development. Since most HOX genes behave as oncogenes or tumor suppressors in human cancer, a better comprehension of their upstream regulators and downstream targets contributes to elucidating the function of HOX genes in cancer development. In addition, targeting HOX genes may imply therapeutic potential. Recently, novel therapies such as monoclonal antibodies targeting tyrosine receptor kinases, small molecular chemical inhibitors, and small interfering RNA strategies, are difficult to implement for targeting transcriptional factors on account of the dual function and pleiotropic nature of HOX genes-related molecular networks. This paper summarizes the current state of knowledge on the roles of HOX genes in human cancer and emphasizes the emerging importance of HOX genes as potential therapeutic targets to overcome the limitations of present cancer therapy.

The Prognostic Value and Function of HOXB5 in Acute Myeloid Leukemia.

BackgroundCurrently, cytogenetic and genetic markers are the most important for risk stratification and treatment of patients with acute myeloid leukemia (AML). Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. Therefore, the identification of new AML biomarkers is useful in the prognosis and monitoring of AML and contributes to a better understanding of the molecular basis of the disease. Homeobox (HOX) genes are transcription factors that lead to cell differentiation blockade and malignant self-renewal. However, the roles of HOX genes in AML are still not fully understood and need further exploration, which may provide new strategies for the prognosis and monitoring of AML.MethodsWe analyzed the RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA), VIZOME, GSE13159, and GSE9476 cohorts. Analyses were performed with GraphPad 7, the R language, and several online databases. We applied quantitative polymerase chain reaction, Western Blotting, CCK8 cell proliferation assays, and flow cytometry to verify the conclusions of the bioinformatics analysis.ResultsWe identified HOXB5 as the only gene among the HOX family that was not only elevated in AML but also a significant prognostic marker in AML patients. HOXB5 was highly expressed in AML patients with NPM1, FLT3, or DNMT3A mutations and was expressed at the highest level in patients with NPM1-FLT3-DNMT3A triple-mutant AML. Gene Ontology analysis and gene set enrichment analysis revealed that HOXB5 showed a negative correlation with the myeloid cell differentiation signature and that the tumor necrosis factor/nuclear factor κB signaling pathway was involved in the molecular mechanism. Moreover, we performed in silico protein–protein interaction analysis and 450K TCGA DNA methylation data analysis and found that HOXB5 interacted with two HOX genes (HOXA7 and HOXB4) that were commonly regulated by DNA methylation levels.ConclusionHOXB5 is associated with the malignant development of AML and may be a treatment target and biomarker for AML prognosis prediction.

Abstract 4612: HOXA13 drives hepatocytes proliferation and liver tumorigenesis in mice

Abstract Introduction: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third most common cause of cancer related mortality worldwide. For patients suffering from advanced stage disease, the few therapeutic options available are not curative and improve patient survival by only a few months. Therefore, new molecular targets that can be explored as therapeutic options are highly needed. Class I Homeobox (HOX) genes are fundamental components of embryonic patterning and morphogenesis, with expression persisting into adulthood. They are also implicated in neoplastic transformations. However, the role of HOX genes is poorly understood and the functional relationship between the malignant phenotype and abnormal expression of HOX genes is still unclear. In this study we sought to define the role of the HOXA13 gene in hepatocarcinogenesis using in vivo models. Methods: To unravel the molecular mechanism of HOXA13 driven tumorigenesis in liver and its direct oncogenicity in vivo, a murine model of HOXA13 overexpression in liver was generated using hydrodynamic injection coupled with a transposase system. This model led to the stable and specific HOXA13 expression in C57BL6\J mouse hepatocytes up to 5 months post injection. Mouse phenotype was followed over time, from 2 weeks up to 1 year post injection. 16 mice (8 for CTRL vector and 8 for HOXA13) were injected and sacrificed for every time point. RNA sequencing was performed to monitor the transcriptomic changes over time. Results: 1 year post injection 50% (4/8) of the injected mice with HOXA13 developed liver tumors of various histological grades and types, from very well differentiated HCCs to very highly undifferentiated and cholangiocarcinoma like nodules. HOXA13 overexpression in the liver led to highly proliferative hepatocytes after only 2 weeks and the proliferative phenotype was maintained until 5 months post injection, when pre neoplastic lesions began to form. HOXA13 overexpression correlated not only with proliferation but also with the DNA damage marker yH2AX, suggesting a possible mechanism of tumorigenesis driven by genome instability. Gene set enrichment analysis of RNA-seq performed on whole liver extracts of 2 week old mice and tumors showed that the main pathways involved in HOXA13 expression are cell cycle, in particular G2/M transition and mitotic assembly checkpoint, angiogenesis, TP53 pathway, IL6JAKSTAT3 signaling, Notch signaling and epithelial to mesenchymal transition. Conclusion: Our study highlights the key role of HOXA13 as a potential novel oncogene in HCC development and suggests possible mechanisms through which it drives liver tumorigenesis. We expect that the generated data in vivo, coupled with mass spectrometry and ChIP sequencing experiments performed in vitro, will further help us identify downstream effectors of HOXA13 thus providing new potential therapeutic targets for HCC. Citation Format: Gaia Bianco, Hesam Montazeri, Luca Quagliata, Tracy O'Connor, Ursula Ehmer, Rupert Oellinger, Mathias Matter, Christofori Gerhard M., Charlotte K.Y. Ng, Salvatore Piscuoglio, Mathias Heikenwaelder, Luigi M. Terracciano. HOXA13 drives hepatocytes proliferation and liver tumorigenesis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4612.

Prognostic significance of MEOX2 in gliomas

Gliomas are the most common malignant primary tumors in the central nervous system and have variable predictive clinical courses. Glioblastoma, the most aggressive form of glioma, is a complex disease with unsatisfactory therapeutic solutions and a very poor prognosis. Some processes at stake in gliomagenesis have been discovered but little is known about the role of homeobox genes, even though they are highly expressed in gliomas, particularly in glioblastoma. Among them, the transcription factor Mesenchyme Homeobox 2 (MEOX2) had previously been associated with malignant progression and clinical prognosis in lung cancer and hepatocarcinoma but never studied in glioma. The aim of our study was to investigate the clinical significance of MEOX2 in gliomas. We assessed the expression of MEOX2 according to IDH1/2 molecular profile and patient survival among three different public datasets: The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas (CGGA) and the US National Cancer Institute Repository for Molecular Brain Neoplasia Data (Rembrandt). We then evaluated the prognostic significance of MEOX2 protein expression on 112 glioma clinical samples including; 56 IDH1 wildtype glioblastomas, 7 IDH1 wild-type lower grade gliomas, 49 IDH1 mutated lower grade gliomas. Survival rates were estimated by the Kaplan-Meier method followed by uni/multivariate analyses. We demonstrated that MEOX2 was one of the transcription factors most closely associated with overall survival in glioma. Moreover, MEOX2 expression was associated with IDH1/2 wildtype molecular subtype and was significantly correlated with overall survival of all gliomas and, more interestingly, in lower grade glioma. To conclude, our results may be the first to provide insight into the clinical significance of MEOX2 in gliomas, which is a factor closely related to patient outcome. MEOX2 could constitute an interesting prognostic biomarker, especially for lower grade glioma.

Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration.

Cardiovascular diseases are the most common cause of human death in the developing world. Extensive evidence indicates that various toxic environmental factors and unhealthy lifestyle choices contribute to the risk, incidence and severity of cardiovascular diseases. Alterations in the genetic level of myocardium affects normal heart development and initiates pathological processes leading to various types of cardiac diseases. Homeobox genes are a large and highly specialized family of closely related genes that direct the formation of body structure, including cardiac development. Homeobox genes encode homeodomain proteins that function as transcription factors with characteristic structures that allow them to bind to DNA, regulate gene expression and subsequently control the proper physiological function of cells, tissues and organs. Mutations in homeobox genes are rare and usually lethal with evident alterations in cardiac function at or soon after the birth. Our understanding of homeobox gene family expression and function has expanded significantly during the recent years. However, the involvement of homeobox genes in the development of human and animal cardiac tissue requires further investigation. The phenotype of human congenital heart defects unveils only some aspects of human heart development. Therefore, mouse models are often used to gain a better understanding of human heart function, pathology and regeneration. In this review, we have focused on the role of homeobox genes in the development and pathology of human heart as potential tools for the future development of targeted regenerative strategies for various heart malfunctions.

Molecular mechanisms in the control of limb regeneration: the role of homeobox genes.

Axolotls are unique among vertebrates in their ability to regenerate lost appendages as adults. They provide the opportunity to study the mechanism of regeneration in vertebrates and are an inspiration to pursue the goal of appendage regeneration in humans. In this article, we review data on the role of homeobox-containing genes in the regulation of limb regeneration. As a group, these genes are important in pattern formation in the primary body axis, developing limbs and regenerating limbs. To date, a total of 22 homeobox genes have been identified as being expressed in regenerating limbs. Nearly all of these are also expressed during limb regeneration, further supporting the view that limb development and regeneration involve similar regulatory mechanisms. Our recent results on the expression of HoxA genes demonstrate that once a blastema has formed, subsequent outgrowth and pattern formation are similar to those of limb development. In contrast to developing limbs, reexpression of the HoxA genes in regeneration occurs by a non-colinear mechanism that likely is related to the necessity of mature limb cells to undergo dedifferentiation in order to give rise to the blastema. These studies also indicate that the pattern is respecified by a distal-first mechanism during regeneration in contrast to the apparent proximal-to-distal sequence observed in developing limbs. Expression of the HoxA genes is altered coordinately in response to retinoic acid in a manner consistent with the transformation of a distal blastema to a proximal blastema. Given the recent increase in studies of the molecules involved in regeneration, it is likely that many of the functionally important regeneration genes will be identified and characterized in the near future.

Comparative transcriptome analysis reveals potentially novel roles of Homeobox genes in adipose deposition in fat-tailed sheep

Adipose tissues are phenotypically, metabolically and functionally heterogeneous based on the sites of their deposition. Undesirable fat deposits in the body are often detrimental to animal and human health. To unravel the potential underlying mechanisms governing accumulation of adipose tissues in various regions of the body, i.e., subcutaneous (SAT), visceral (VAT) and tail (TAT), we profiled transcriptomes from Tan sheep, a Chinese indigenous breed with notable fat tail using RNA-seq. Upon comparison, we identified a total of 1,058 differentially expressed genes (DEGs) between the three adipose types (218, 324, and 795 in SAT/VAT, SAT/TAT, and VAT/TAT, respectively), from which several known key players were identified that are involved in lipid metabolic process, Wnt signals, Vitamin A metabolism, and transcriptional regulation of adipocyte differentiation. We also found that many elevated genes in VAT were notably enriched for key biological processes such as cytokine secretion, signaling molecule interaction and immune systems. Several developmental genes including HOXC11, HOXC12 and HOXC13, and adipose-expressed genes in the tail region, such as HOTAIR_2, HOTAIR_3 and SP9 were specially highlighted, indicating their strong associations with tail fat development in fat-tailed sheep. Our results provide new insight into exploring the specific fat deposition in tail, also contribute to the understanding of differences between adipose depots.

Role of homeobox genes in tooth morphogenesis: a review.

In oral cavity, disturbances due to genetic alterations may range from lack of tooth development to morphological defects. Due to technical advances in genetic engineering and molecular biology, valuable information regarding dentofacial growth could be studied in detailed manner. This helped us to explain the aetiology and pathogenesis of many dentofacial disorders. The success in treatment lies first in determining the aetiology of tooth anomalies and finally differentiating the effect of genes and environment on the orofacial diseases of that particular individual. Several genes belonging to class II homeobox families are expressed during odontogenesis however homeobox genes are not directly imvolved in tooth formation as they are not directly expressed in the first branchial arch derivatives.

The ninth International Conference of Anticancer Research, 6-10 October 2014, Sithonia, Greece.

The ninth conference of the International Institute for Anticancer Research, held in Sithonia, Greece in October 2014, included over 700 abstracts presented in 79 separate sessions and featured a wide range of topics in basic and clinical cancer research. This report describes a small but representative sample of these sessions. It covers some recent developments in research into the basic signal transduction pathways involved in carcinogenesis; a special session on the role of homeobox genes in cancer development; and clinical sessions covering advances in breast cancer, haematological cancers, and chemotherapy.

A HoxD11 Homeobox Gene Mutation Associated With Congenital Absent Radius But Without The Thrombocytopenia Of The TAR Syndrome Or a HoxA11 Mutation

HoxA11 and HoxD11 are homeobox genes critical for normal development of the forearm and thus are potential candidate genes for involvement in the pathogenesis of the thrombocytopenia/absent radius (TAR) syndrome. However, we previously reported an absence of coding sequence mutations in either HoxA11 or HoxD11 in a series of 10 unrelated TAR syndrome patients (Fleischman RA et al., Br J Haematol., 116:367-75, 2002). Despite this negative finding, interest in the potential role of homeobox genes in the TAR syndrome has been supported by a report of a HoxA11 mutation occurring in two kindreds with amegakaryocytic thrombocytopenia and radio-ulnar synostosis, a less pronounced more proximal pattern of radial malformation (Thompson AA and Nguyen LT. Nat Genet., 26:397-8, 2000). Unlike HoxA11, however, no mutations in the human HoxD11 gene have been described thus far that would help elucidate the potential role of this paralogous gene in megakaryopoiesis or the TAR syndrome. We now describe a novel mutation in human HoxD11 that results in a polyalanine sequence expansion, (GCG)6→ (GCG)8, and report that this mutation is associated with a unilateral absent radius in the affected propositus. A familial syndrome is suggested in this kindred, moreover, by the prior observation of a bilateral absent radius in a deceased maternal aunt. This mutation was not present in more than 100 unrelated normal subjects or 8 other unrelated individuals with sporadic absence of the radius. Two other living maternal relatives also carried the mutation but did not exhibit any radial defects, a finding consistent with autosomal dominance with incomplete penetrance, an inheritance pattern reported for short polyalanine expansion mutations in the related homeobox gene HoxD13 which cause synpolydactyly. In contrast to the reported HoxA11 mutation, however, neither the propositus nor the mutation carriers of this HoxD11 mutation exhibited thrombocytopenia or any other cytopenias or congenital defect. The results suggest that at least one class of mutation in human HoxD11 may be sufficient to cause an absent radius syndrome but unlike the reported HoxA11 mutation, does not adversely affect megakaryopoiesis. The findings further suggest that additional studies of the TAR syndrome may be necessary to exclude as yet undetected non-coding mutations in promoter or enhancer sequences that alter the expression of HoxA11, HoxD11 or other homeobox genes critical for radial development and/or megakaryopoiesis. This work was supported by a VA Merit Award. Disclosures: No relevant conflicts of interest to declare.

Role of homeobox genes in the hypothalamic development and energy balance

Homeobox genes contribute to the regionalization, patterning and cell differentiation during embryogenesis and organ development. During mammalian embryonic development, homeobox genes, including orthopedia (Otp), a brain-specific homeobox transcription factor (Bsx) and a thyroid transcription factor-1 (TTF-1), are expressed in the hypothalamus. The genetic ablation of these genes indicated that Otp and TTF-1 are essential for the normal morphological development of the hypothalamus, including the arcuate nucleus (ARC), whereas Bsx is not required. In the adult stage, Bsx and TTF-1 continue to be expressed in the hypothalamus, including the ARC, and serve as transcription factors of neuropeptide Y and agouti-related protein.The expression of hypothalamic Bsx and TTF-1 can be altered by the feeding state and appetite regulatory hormones such as ghrelin and leptin. Although Bsx and TTF-1 are essential for normal feeding behavior in adult mice, they exert different effects on the expression of hypothalamic pro-opiomelanocortin (POMC) and body weight homeostasis. Thus, the hypothalamic homeobox genes may contribute to the dissociation of food intake and body weight via AgRP-POMC neurons.

315. HOMEOBOX GENES ARE DIFFERENTIALLY EXPRESSED IN PRIMARY VILLOUS AND EXTRAVILLOUS TROPHOBLAST CELL LINEAGES DURING EARLY PREGNANCY

During human placental development trophoblast cells differentiate along either the villous cytotrophoblast (VCT) lineage to form the syncytiotrophoblast (ST) or the invasive extravillous cytotrophoblast (EVCT) lineage (1). Abnormalities in early differentiation processes are characteristic of poor placentation, which is associated with fetal growth restriction (FGR) and pre-eclampsia (PE), the major clinical complications of human pregnancy (2). A large family of homeobox gene transcription factors controls “cell-fate decisions” during development (3), but the expression profile and role of homeobox genes in the human trophoblast cell lineages is not well understood. The aim of the study was to determine homeobox gene expression in primary cultures of mononuclear VCT (2h) and EVCT (2 h) obtained from first trimester human chorionic villi of 8–12 weeks of gestation and in vitro differentiated ST (72 h) and invasive EVCT (48 h), respectively. The isolation and characterization of freshly isolated VCT, EVCT and in vitro differentiated ST and invasive EVCT were performed as described previously (1,4). The homeobox gene mRNA profile was performed using PCR arrays in a pooled sample of VCT and EVCT (n = 6 in each group) and further validated by real-time PCR. Homeobox gene expression studies revealed MSX2 mRNA levels were the highest in VCT (2 h) but undetectable in EVCT (2 h). Further comparisons of homeobox gene expression in in vitro differentiated ST to invasive EVCT showed marked increase in MSX2, DLX3, DLX4 and MEIS1 mRNA levels in ST, which are regulators of cellular differentiation in many studies. Homeobox genes HLX and HHEX, which are implicated in regulating cellular proliferation showed decreased mRNA levels in ST compared to invasive EVCT. Our results demonstrated several known placental and novel homeobox genes are differentially expressed in trophoblast cell lineages. Functional studies of these candidate genes will provide a better understanding of the molecular mechanisms of early placental development. (1) Tarrade et al. (2001) Lab Invest. 81, 1199–1211.(2) LokeYW and King A (1995) Cell Biology and Immunology, Cambridge ed.(3) J Cross et al. (2002) Recent Progress in Hormone Research 57: 221–234.(4) Handschuh et al. (2007) Placenta, 28, 175–184.

Expression of the Brain Transcription Factor OTX1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive Non-Hodgkin Lymphoma

The roles in brain development. Previous studies have shown the association between OTX2 and OTX1 with anaplastic and desmoplastic medulloblastomas, respectively. Here, we investigated OTX1 and OTX2 expression in Non-Hodgkin Lymphoma (NHL) and multiple myeloma. A combination of semiquantitative RT-PCR, Western blot, and immunohistochemical analyses was used to measure OTX1 and OTX2 levels in normal lymphoid tissues and in 184 tumor specimens representative of various forms of NHL and multiple myeloma. OTX1 expression was activated in 94% of diffuse large B-cell lymphomas, in all Burkitt lymphomas, and in 90% of high-grade follicular lymphomas. OTX1 was undetectable in precursor-B lymphoblastic lymphoma, chronic lymphocytic leukemia, and in most marginal zone and mantle cell lymphomas and multiple myeloma. OTX2 was undetectable in all analyzed malignancies. Analysis of OTX1 expression in normal lymphoid tissues identified a subset of resting germinal center (GC) B cells lacking PAX5 and BCL6 and expressing cytoplasmic IgG and syndecan. About 50% of OTX1(+) GC B cells co-expressed CD10 and CD20. This study identifies OTX1 as a molecular marker for high-grade GC-derived NHL and suggests an involvement of this transcription factor in B-cell lymphomagenesis. Furthermore, OTX1 expression in a subset of normal GC B cells carrying plasma cell markers suggests its possible contribution to terminal B-cell differentiation.

Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals

Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators during developmental processes such as regional specification, patterning, and differentiation. In this review, we summarize the expression pattern, loss- and/or gain-of-function mouse models, and naturally occurring mouse and human mutations of known homeobox genes required for the development of ectodermal appendages.

Parathyroid tumor development involves deregulation of homeobox genes

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear. Recent studies have suggested that menin may act as a scaffold protein to coordinate gene transcription, and that menin is an oncogenic cofactor for homeobox (HOX) gene expression in hematopoietic cancer. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play important roles in the development of cancer. Therefore, we hypothesized that specific HOX genes were regulated by menin in parathyroid tumor development. Utilizing quantitative TaqMan RT-PCR, we compared expression profiles of the 39 HOX genes in human familial MEN1 (fMEN1) parathyroid tumors and sporadic parathyroid adenomas with normal samples. We identified a large set of 23 HOX genes whose deregulation is specific for fMEN1 parathyroid tumors, and only 5 HOX genes whose misexpression are specific for sporadic parathyroid tumor development. These findings provide the first evidence that loss of the MEN1 tumor suppressor gene is associated with deregulation of specific HOX gene expression in the development of familial human parathyroid tumors. Our results strongly reinforce the idea that abnormal expression of developmental HOX genes can be critical in human cancer progression.

Pour une approche génétique et expérimentale de la croissance squelettique cranio-faciale : étude du rôle de l'homéogène divergent Msx1

Tooth agenesis and clef palate are associated to the mutation of the Msx1 homeobox genes, highlighting the pivotal role of homeobox genes during the initial development of the craniofacial skeleton. Msx1 also controls the terminal differentiation of mineralised tissues forming cells. Recently, a Msx1 antisense RNA has been identified which inhibits Msx1 protein expression in odontoblastic cells. In order to investigate the role of Msx1 gene and its antisense RNAs during the late developmental stages of the craniofacial bone formation, the expression pattern of Msx1 protein, sense and antisense transcripts and the aspects of bone growth have been studied in post-natal normal and Msx1 knock-in mutant mice. Msx1 protein was strongly expressed in preosteoblasts of specific bone sites such as the basal mandible. At the same bone sites, bone growth was impaired or markedly decreased in knock-in mice. The comparison between the various expression patterns of Msx1 protein, sense and antisense RNAs suggests that the site-specific action of Msx1 protein on bone growth and craniofacial morphogenesis and that Msx1 protein level could be controlled by the local ratio of Msx1 sense and antisense RNAs. Regarding our experimental data and hypothesis, a clinical study of patients with MSX1 mutation will be performed in order to better characterize the abnormalities of the craniofacial skeleton growth.

Study on tooth development, past, present, and future.

For decades, the understanding of craniofacial development has been a central issue in odontology and developmental biology. As a consequence, a significant number of deformities are being studied for their variety of genotype and phenotype. Although there is little doubt about the essential roles of homeobox genes, transcription factors, and growth factors, we now know at least the fundamental strategy of craniofacial biology. The tooth as an organ performs a whole range of functions, each of which is truly indispensable for the maintenance of life. The possession of teeth is, therefore, obviously coupled with the complication of the natural structure of an individual organism. In the following, we shall focus on a brief history of tooth studies and some suggestions for obtaining a full understanding of teeth in the future.

Role of homeobox genes in normal mammary gland development and breast tumorigenesis.

The role of homeobox-containing genes in embryogenesis and organogenesis is well documented. Also, a sizeable body of evidence has accumulated and supports the fact that homeobox genes, when dysregulated, are involved in tumorigenesis. However, the precise mechanisms of homeobox gene functions are largely unknown. The mammary gland, in which most maturation occurs postnatally, provides an ideal model for studying the functions of homeobox genes in both development and tumorigenesis. The expression of many homeobox genes has been detected in both normal mammary gland and neoplastic breast tissues. In the normal mammary gland, the expression of homeobox genes is coordinately regulated by hormone and extracellular matrix (ECM) and other unknown factors in a spatial and temporal manner in both stromal and epithelial cells. Animals with misexpressed homeobox genes displayed different extents of defects in ductal proliferation, side branching, and alveoli formation, implying that homeobox genes are important for normal mammary gland development. Recent studies of homeobox genes in breast cancer cells and primary tumors indicate that they may also play a contributory or causal role in tumorigenesis by regulating the cell cycle, apoptosis, angiogenesis, and/or metastasis.

Homeobox genes: going for growth.

The role of homeobox genes and dietary factors in gut growth and differentiation In this issue of Gut , Domon-Dell and colleagues1 report the influence of butyrate on the intestinal homeobox gene Cdx2 [ see page 525 ]. Butyrate is a byproduct of fibre fermentation by colonic bacteria and is known to be a substrate for colonocytes. Over the last few years there has been increasing interest in the function of genes involved in controlling the anatomical relationships between various organs. This article therefore touches on the role of homeobox genes and dietary factors in gut growth and differentiation. The development of multicellular animals is dependent on expression of a hierarchy of genes that sequentially provide increasingly detailed positional information. Many of these genes contain a highly preserved “homeobox” sequence that codes for a DNA binding homeo domain. In insects, a group of such genes—specifying the individual characteristics of body segments and known as homeotic selector genes of the Antp -type (the defining gene is named Antennapaedia )—are clustered in a complex known as the HOM cluster. These are expressed topographically in the same order as they occupy in chromosomal DNA. They are conserved strongly during evolution so that their homologues appear as four paraologous gene complexes known as Hox complexes which specify positional information in mammalian embryos. Other homeobox genes are scattered in …