SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis.

BACKGROUND: Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood. METHODS: Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings. RESULTS: There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies. CONCLUSION: Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

Molecular characterization of early breast cancer onset to understand disease phenotypes in African patients.

Female breast cancer (BC) is the leading cause of cancer-related deaths worldwide with higher mortality rates and early onset in developing countries. The molecular basis of early disease onset is still elusive. We recruited 472 female breast cancer from two sub-Saharan African countries (Cameroon and Congo) between 2007 and 2018 and collected clinical data from these patients. To investigate the molecular drivers of early disease onset, we analyzed publicly available breast cancer molecular data from the cancer genome atlas (TCGA) and the gene expression omnibus (GEO) for copy number alteration, mutation and gene expression. Early BC onset (EOBRCA) (diagnosis before 45 years) was higher in African women compared with the TCGA cohort (51.7% vs 15.6%). The tumor grade, mitotic index, HER2 + phenotype, basal-like phenotype and ki67 were higher in EOBRCA for all cohorts. BC risk factors such as parity, breastfeeding early onset of menarche and use of hormonal contraceptives were significantly associated with EOBRCA (p < 0.05). EOBRCA was equally associated with copy number alterations in several oncogenes including CDH6 and FOXM1 and tumor suppressor including TGM3 and DMBT1 as well as higher TP53 mutation rates (OR: 2.93, p < 0.01). There was a significant enrichment of TGFß signaling in EOBRCA with TGM3 deletions, which was associated with high expression of all SMAD transcription factors as well as WNT ligands. The Frizzled receptors FZD1, FZD4 and FZD6 were significantly upregulated in EOBRCA, suggesting activation of non-canonical WNT signaling. Our data, suggest the implication of TGM3 deletion in early breast cancer onset. Further molecular investigations are warranted in African patients.

The TP63 Gene Polymorphism rs17506395 is Associated with Early Breast Cancer in Cameroon.

BACKGROUND: Breast cancer (BC) is a leading female cancer worldwide and cause of cancer-related death, especially in developing countries. Genetic predispositions to BC development in African population is poorly studied, and meanwhile the SNP rs17506395 in TP63 gene locus has been associated with the development of breast cancer in Asian women, no investigation has been undertaken within African population. We investigated the impact of this polymorphism in a representative African population. METHODS: We undertook a case-control study including 335 women, of which 111 were breast cancer patients and 224 controls. Using blood-derived germline DNA, PCR-RFLP was used to investigate the polymorphism of TP63 gene at rs17506395 locus. Unconditional logistic regression was used to study the association between the TP63 gene polymorphism and risk of BC development. After stratification into different age and ethno-linguistic groups as well as menopausal status, the Cochran-Mantel-Haenszel test was used to measure significance of the associations. RESULTS: Comparing cases with controls, no significant associations between genotype and disease development was observed. Similarly, when cases were stratified according to menopausal status and ethno-linguistic groups, no significant association was observed between genotype and disease development. However, in women of 40 years and below, TT and TG genotypes were associated with breast cancer development. The minor G allele seems to protective against early breast cancer onset OR of 0.5 (95%CI = 0.26-0.94, p = 0.03). CONCLUSION: Our data revealed an association between rs15706395 and the risk of early breast cancer onset. The GG genotype seems to reduce the risk of early breast cancer. Larger studies are needed to confirm the potential of this SNP as biomarker for breast cancer prognostic.
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An 8-year prospective clinical investigation on the survival rate of feldspathic veneers: Influence of occlusal splint in patients with bruxism.

OBJECTIVES: The aim of this study was to perform a 8-year prospective clinical investigation on the survival rate of feldspathic ceramic veneers, as well as analyse the influence of the occlusal splint in patients with parafunctional bruxism. METHODS: Three hundred and sixty-four veneers fabricated using conventional feldspathic ceramic were provided in 64 patients. The patient sample included 40 individuals with bruxism. During the follow-up period, the effect of wearing the occlusal splint on the incidence of failure (fracture and/or debonding) in patients with bruxism was also assessed. The survival rate of veneers was determined using the Kaplan-Meier estimator. Statistical significance was set at p < 0.05 with a confidence interval of 95%. RESULTS: The occurrence of fracture for the feldspathic veneers tested in this study was 7.7%, while only 1.9% of the total number of veneers debonded. The overall survival rate was 93.7% after 3 years, 91% after 5 years, and 87.1% after 8 years. Patients with bruxism using an occlusal splint showed a survival rate of 89.1% after 7 years, while the survival rate in patients with bruxism using no occlusal splint was 63.9% (p < 0.05). CONCLUSION: This study confirmed that feldspathic veneers may represent a suitable clinical solution for indirect aesthetic restorations. Such a treatment may be an option also for those patients affected by bruxism, as long as they regularly wear an occlusal splint. However, patients with bruxism using no occlusal splint may still present a potential high-risk of failure and/or debonding.

Heparan sulfate proteoglycans regulate BMP signalling during neural crest induction.

Bone morphogenetic protein (BMP) signalling is key to many developmental processes, including early regionalisation of the ectoderm. The neural crest is induced here by a combination of BMP and Wnt signals from nearby tissues with many secreted factors contributing to its initial specification at the neural plate border. Gremlin 1 (Grem1) is a secreted BMP antagonist expressed in the neural crest in Xenopus laevis but its function here is unknown. As well as binding BMPs, Grem1 has been shown to interact with heparan sulfate proteoglycans (HSPGs), a family of cell surface macromolecules that regulate a diverse array of signalling molecules by affecting their availability and mode of action. This study describes the impact of HSPGs on the function of Grem1 in neural crest induction. It shows for the first time that Grem1 is required for neural crest development in a two-step process comprising an early HSPG-independent, followed by a late HSPG-dependent phase.

[Prognosis and survival of esophageal cancer in Cameroon: a prognostic study]. / Facteurs pronostiques du cancer de l'œsophage au Cameroun: étude multicentrique.

INTRODUCTION: Esophageal cancer is rare. Poor prognosis is due to delayed diagnosis. Five year survival is less than 20%. This study aimed to investigate the factors associated with survival of patients with esophageal cancer in Cameroon. METHODS: We conducted a prognostic study in the General Hospitals in Yaoundé and in Douala over a period of 11 years from 1 January 2005 to 31 December 2015. The parameters studied were those associated with survival. Survival was established on the basis of the date of diagnosis and of the date of death or of the last visit. SPSS software (Statistical Package for Social Sciences) version 23 allowed for data analysis. Kaplan Meier curve was used to estimate the survival function. Log RankTest allowed for comparison among the different groups. Cox regression helped to highlight the different factors associated with it. Significance level was set at 0.05. RESULTS: We collected data from 49 medical records. The average age of patients was 57.83 years. There was a male predominance (71.4%; n=35) with a sex ratio of 2.49. The follow-up period was 3.2 months. Median survival was 6.67 months (CI 95% [1.33-10.4]) and the average survival time was 7.99 months (CI 95% [4.42-11.17]). Multivariate-adjusted analysis showed that stage IV was a predictive factor of mortality (HR = 2.79; CI95% [1.13-6.89], p = 0.025]). CONCLUSION: Esophageal cancer is a rare disease with poor prognosis. Prognostic factor is the tumor stage.

Medical Education and Leadership in Breastfeeding Medicine.

Physicians' experience with high quality training in breastfeeding during their medical education is historically varied. The process of becoming a board-certified physician entails more than 20 years of education, and although medical school and residency training timelines and courses are relatively standardized across the United States and even internationally, breastfeeding education varies greatly across schools and programs. The Academy of Breastfeeding Medicine (ABM) exists, in part, because historically, physicians have received too little clinical training in breastfeeding and infant nutrition. An overarching goal of ABM, which is a multispecialty organization of doctors around the world, is to educate all maternal-child healthcare professionals, not just physicians, about breastfeeding. Within the field of medicine, family doctors, pediatricians, and obstetrician/gynecologists are considered the most logical source of breastfeeding expertise. However, the need for breastfeeding education goes beyond those providers who have obvious interactions with mothers and babies. We must educate anesthesiologists, surgeons, internists, and psychiatrists, among others. Building pipelines of physicians who are well educated in breastfeeding medicine allows more effective collaboration and care of mothers and infants among providers in various medical and surgical specialties as well as between doctors and other healthcare providers. This evidence-based education needs to be multifaceted, with didactic curricula for a strong knowledge base complemented by clinical experiences for skill development and application. Clinical knowledge and skills can also be reinforced during nonclinical opportunities in teaching, research, advocacy, and professional development. In this article, we describe a foundational framework for physician education in breastfeeding medicine as well as several creative noncurricular opportunities to develop breastfeeding expertise in future physician leaders. We conclude with a case study.

Severe tetracycline dental discoloration: Restoration with conventional feldspathic ceramic veneers. A clinical report.

The treatment of severe tetracycline discoloration is a challenge for the dentist. There are several treatment options and one of the most effective is the use of feldspathic veneers. The aim of this clinical case was to carry out the replacement with conventional feldspathic ceramic veneers on a patient with highly stained teeth (grade IV tetracycline) by a minimally invasive approach. Clinical examination revealed gingival retraction, color change of the veneers, ceramic cracked of 1.1 and 1.3 and incisal wear in lower anterior teeth. The decision was to retreat with feldspathic ceramic veneers from 1.6 to 2.6. Premolars and first molars were included because its dark color intensifies the width buccal corridors. Also, the restoration with veneers from 3.3 to 4.3 was considered. Firstly, the veneers were removed and the color was selected by the Vitapan 3D Master guide (Vita Zahnfabrick, Bad Säckingen, Germany). Mock-up was made to evaluate aesthetic, phonetic and functional parameters. Then, teeth were prepared through the mock-up in order to reduce the minimal amount of dental tissue possible. Opaque dentine mass of microhybrid composite (Esthet-X A2O, Dentsply Sirona, Konstanz, Germany) was placed to mask the most intense stains. The definitive impressions were taken with silicone (Aquasil Ultra XLV, Dentsply Sirona, Konstanz, Germany) were taken to fabricate conventional feldsphatic ceramic veneers (Noritake kisai Co, Ltd. Japan) by the parallel stratification masking technique. For cementing, an opaque cement was selected from the try-in tests (Calibra, Dentsply Sirona, Konstanz, Germany) and the composite was silicatized with an air-abrasion device. A favorable and minimally invasive result was achieved to treat grade IV tetracycline stains, surpassing the patient's aesthetic expectations and functional needs. Key words:Porcelain veneer, tetracycline teeth, minimally invasive, masking, opaque composite.

Molecular specification of germ layers in vertebrate embryos.

In order to generate the tissues and organs of a multicellular organism, different cell types have to be generated during embryonic development. The first step in this process of cellular diversification is the formation of the three germ layers: ectoderm, endoderm and mesoderm. The ectoderm gives rise to the nervous system, epidermis and various neural crest-derived tissues, the endoderm goes on to form the gastrointestinal, respiratory and urinary systems as well as many endocrine glands, and the mesoderm will form the notochord, axial skeleton, cartilage, connective tissue, trunk muscles, kidneys and blood. Classic experiments in amphibian embryos revealed the tissue interactions involved in germ layer formation and provided the groundwork for the identification of secreted and intracellular factors involved in this process. We will begin this review by summarising the key findings of those studies. We will then evaluate them in the light of more recent genetic studies that helped clarify which of the previously identified factors are required for germ layer formation in vivo, and to what extent the mechanisms identified in amphibians are conserved across other vertebrate species. Collectively, these studies have started to reveal the gene regulatory network (GRN) underlying vertebrate germ layer specification and we will conclude our review by providing examples how our understanding of this GRN can be employed to differentiate stem cells in a targeted fashion for therapeutic purposes.

Coco regulates dorsoventral specification of germ layers via inhibition of TGFß signalling.

One of the earliest steps in embryonic development is the specification of the germ layers, the subdivision of the blastula embryo into endoderm, mesoderm and ectoderm. Maternally expressed members of the Transforming Growth Factor ß (TGFß) family influence all three germ layers; the ligands are required to induce endoderm and mesoderm, whereas inhibitors are required for formation of the ectoderm. Here, we demonstrate a vital role for maternal Coco, a secreted antagonist of TGFß signalling, in this process. We show that Coco is required to prevent Activin and Nodal signals in the dorsal marginal side of the embryo from invading the prospective ectoderm, thereby restricting endoderm- and mesoderm-inducing signals to the vegetal and marginal zones of the pre-gastrula Xenopus laevis embryo.

A meta-analysis of male breast cancer in Africa.

To characterize male breast cancer in Africa in recent decades, we systematically reviewed literature and conducted a meta-analysis of available data on male breast cancer in Africa. A paper was included if both male and female breast cancer were available. If two publications covered the same geographic area, only the publication with a longer study period was included. Random effects models and mixed effect meta-regressions were used to analyze data of 1201 male and 36,172 female breast cancer patients from 27 African countries. We showed that the male-to-female breast cancer ratio was 0.042 overall and it has decreased in recent years. Additionally, male breast cancer patients in Africa had the disease at age 54.6 on average, 7 years older than female patients. In conclusion, male breast cancers in Africa are characterized as late onset and male-to-female breast cancer ratio in Africa is higher than populations in developed countries.

Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

Neural induction is the first step in the formation of the vertebrate central nervous system. The emerging consensus of the mechanisms underlying neural induction is the combined influences from inhibiting bone morphogenetic protein (BMP) signaling and activating fibroblast growth factor (FGF)/Erk signaling, which act extrinsically via either autocrine or paracrine fashions. However, do intrinsic forces (cues) exist and do they play decisive roles in neural induction? These questions remain to be answered. Here, we have identified a novel neural initiator, neuronatin (Nnat), which acts as an intrinsic factor to promote neural fate in mammals and Xenopus. ESCs lacking this intrinsic factor fail to undergo neural induction despite the inhibition of the BMP pathway. We show that Nnat initiates neural induction in ESCs through increasing intracellular Ca(2+) ([Ca(2+) ](i)) by antagonizing Ca(2+) -ATPase isoform 2 (sarco/endoplasmic reticulum Ca(2+) -ATPase isoform 2) in the endoplasmic reticulum, which in turn increases the phosphorylation of Erk1/2 and inhibits the BMP4 pathway and leads to neural induction in conjunction with FGF/Erk pathway.

PRDC regulates placode neurogenesis in chick by modulating BMP signalling.

The epibranchial placodes generate the neurons of the geniculate, petrosal, and nodose cranial sensory ganglia. Previously, it has been shown that bone morphogenetic proteins (BMPs) are involved in the formation of these structures. However, it has been unclear as to whether BMP signalling has an ongoing function in directing the later development of the epibranchial placodes, and how this signalling is regulated. Here, we demonstrate that BMPs maintain placodal neurogenesis and that their activity is modulated by a member of the Cerberus/Dan family of BMP antagonists, Protein Related to Dan and Cerberus (PRDC). We find that Bmp4 is expressed in the epibranchial placodes while Bmp7 and PRDC are expressed in the pharyngeal pouches. The timing and regional expression of these three genes suggest that BMP7 is involved in inducing placode neurogenesis and BMP4 in maintaining it and that BMP activity is modulated by PRDC. To investigate this hypothesis, we have performed both gain- and loss- of-function experiments with PRDC and find that it can modulate the BMP signals that induce epibranchial neurogenesis: a gain of PRDC function results in a loss of Bmp4 and hence placode neurogenesis is inhibited; conversely, a loss of PRDC function induces ectopic Bmp4 and an expansion of placode neurogenesis. This modulation is therefore necessary for the number and positioning of the epibranchial neurons.

DRAGON, a bone morphogenetic protein co-receptor.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)beta superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGFbeta ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGFbeta signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGFbeta ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling.

Segmental identity and cerebellar granule cell induction in rhombomere 1.

BACKGROUND: Cerebellar granule cell precursors are specifically generated within the hindbrain segment, rhombomere 1, which is bounded rostrally by the midbrain/hindbrain isthmus and caudally by the boundary of the Hoxa2 expression domain. While graded signals from the isthmus have a demonstrable patterning role within this region, the significance of segmental identity for neuronal specification within rhombomere 1 is unexplored. We examined the response of granule cell precursors to the overexpression of Hoxa2, which normally determines patterns of development specific to the hindbrain. How much does the development of the cerebellum, a midbrain/hindbrain structure, reflect its neuromeric origin as a hindbrain segment? RESULTS: We show that a Gbx2-positive, Otx2-/Hoxa2-negative territory corresponding to rhombomere 1 forms prior to an identifiable isthmic organiser. Early global overexpression of Hoxa2 at embryonic day 0 has no effect on the expression of isthmic signalling molecules or the allocation of rhombomere 1 territory, but selectively results in the loss of granule cell markers at embryonic day 6 and the depletion of cell bodies from the external granule cell layer. By comparison the trochlear nucleus and locus coeruleus form normally in ventral rhombomere 1 under these conditions. Microsurgery, coupled with electroporation, to target Hoxa2 overexpression to rhombic lip precursors, reveals a profound, autonomous respecification of migration. Rhombic lip derivatives, normally destined to occupy the external granule cell layer, violate the cerebellar boundary to form a ventrolateral nucleus in a position comparable to that occupied by rhombic lip derived neurons in rhombomere 2. CONCLUSIONS: Different overexpression strategies reveal that the recognition of migration cues by granule cell precursors is dependent on their identity as rhombomere 1 derivatives. Segmental patterning cues operate autonomously within the rhombic lip precursor pool. By contrast, a subset of coextensive nuclei is refractory to ectopic Hoxa2 and is presumably induced solely by isthmic organiser activity. Thus, graded (isthmic) and segmental mechanisms may operate exclusively of one another in the specification of different neuronal populations within rhombomere 1. The early designation of an Otx2-negative, Hoxa2-negative region, prior to the appearance of the isthmic organiser, is a key initial step in the specification of the cerebellum.

DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties.

DRG11, a transcription factor expressed in embryonic dorsal root ganglion (DRG) and dorsal horn neurons, has a role in the development of sensory circuits. We have used a genomic binding strategy to screen for the promoter region of genes regulated by DRG11. One gene with a promoter region binding to the DNA binding domain of DRG11 encodes a novel membrane-associated [glycosyl-phosphatidylinositol (GPI)-anchored] protein that we call DRAGON. DRAGON expression is transcriptionally regulated by DRG11, and it is coexpressed with DRG11 in embryonic DRG and spinal cord. DRAGON expression in these areas is reduced in DRG11 null mutants. DRAGON is expressed, however, in the neural tube before DRG11, and unlike DRG11 it is expressed in the brain and therefore must be regulated by other transcriptional regulatory elements. DRAGON shares high sequence homology with two other GPI-anchored membrane proteins: the mouse ortholog of chick repulsive guidance molecule (mRGM), which is expressed in the mouse nervous system in areas complementary to DRAGON, and DRAGON-like muscle (DL-M), the expression of which is restricted to skeletal and cardiac muscle. A comparative genomic analysis indicates that the family of RGM-related genes--mRGM, DRAGON, and DL-M--are highly conserved among mammals, zebrafish, chick, and Caenorhabditis elegans but not Drosophila. DRAGON, RGM, and DL-M mRNA expression in the zebrafish embryo is similar to that in the mouse. Neuronal cell adhesion assays indicate that DRAGON promotes and mRGM reduces adhesion of mouse DRG neurons. We show that DRAGON interacts with itself homophilically. The dynamic expression, ordered spatial localization, and adhesive properties of the RGM-related family of membrane-associated proteins are compatible with specific roles in development.

Fluorescent labeling of endothelial cells allows in vivo, continuous characterization of the vascular development of Xenopus laevis.

Appropriate blood supply and vascular development are necessary in development and in cancer, heart disease, and diabetes. Here, we report the use of DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL) to label endothelial cells and characterize the vasculature of live Xenopus embryos. The atlas we have created provides a detailed map of normal vascular development against which perturbations of normal patterning can be compared. By following the development of the intersomitic vessels in real-time, we show that, while rostrocaudal gradient of maturing intersomitic vessels occurs, it is not absolute. In addition, the comparative study of the ontogeny of nerve bundles from the spinal cord of transgenic Xenopus embryos expressing green fluorescent protein in the nervous system and blood vessels demonstrates a strong anatomical correlation in neurovascular development. These studies provide the basis for understanding how the vascular system forms and assumes its complicated stereotypical pattern in normal development and in disease.

Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor.

Patterning of the pre-gastrula embryo and subsequent neural induction post-gastrulation are very complex and intricate processes of which little, until recently, has been understood. The earliest decision in neural development, the choice between epidermal or neural fates, is regulated by bone morphogenetic protein (BMP) signaling within the ectoderm. Inhibition of BMP signaling is sufficient for neural induction. Many secreted BMP inhibitors are expressed exclusively within the organizer of the Xenopus gastrula embryo and therefore are predicted to act as bona fide endogenous neural inducers. Other cell-autonomous inhibitors of the BMP pathway are more widely expressed, such as the inhibitory Smads, Smad6 and Smad7. In this report we describe the biological and biochemical characterization of 51-B6, a novel member of Cerberus/Dan family of secreted BMP inhibitors, which we identified in a screen for Smad7-induced genes. This gene is expressed maternally in an animal to vegetal gradient, and its expression levels decline rapidly following gastrulation. In contrast to known BMP inhibitors, 51-B6 is broadly expressed in the ectoderm until the end of gastrulation. The timing, pattern of expression, and activities of this gene makes it unique when compared to other BMP/TGFbeta/Wnt secreted inhibitors which are expressed only zygotically and maintained post-gastrulation. We propose that a function of 51-B6 is to block BMP and TGFbeta signals in the ectoderm in order to regulate cell fate specification and competence prior to the onset of neural induction. In addition, we demonstrate that 51-B6 can act as a neural inducer and induce ectopic head-like structures in neurula staged embryos. Because of this embryological activity, we have renamed this clone Coco, after the Spanish word meaning head.

Gene profiling during neural induction in Xenopus laevis: regulation of BMP signaling by post-transcriptional mechanisms and TAB3, a novel TAK1-binding protein.

The earliest decision in vertebrate neural development is the acquisition of a neural identity by embryonic ectodermal cells. The default model for neural induction postulates that neural fate specification in the vertebrate embryo occurs by inhibition of epidermal inducing signals in the gastrula ectoderm. Bone morphogenetic proteins (BMPs) act as epidermal inducers, and all identified direct neural inducers block BMP signaling either intra- or extracellularly. Although the mechanism of action of the secreted neural inducers has been elucidated, the relevance of intracellular BMP inhibitors in neural induction is not clear. In order to address this issue and to identify downstream targets after BMP inhibition, we have monitored the transcriptional changes in ectodermal explants neuralized by Smad7 using a Xenopus laevis 5000-clone gastrula-stage cDNA microarray. We report the identification and initial characterization of 142 genes whose transcriptional profiles change in the neuralized explants. In order to address the potential involvement during neural induction of genes identified in the array, we performed gain-of-function studies in ectodermal explants. This approach lead to the identification of four genes that can function as neural inducers in Xenopus and three others that can synergize with known neural inducers in promoting neural fates. Based on these studies, we propose a role for post-transcriptional control of gene expression during neural induction in vertebrates and present a model whereby sustained BMP inhibition is promoted partly through the regulation of TGFbeta activated kinase (TAK1) activity by a novel TAK1-binding protein (TAB3).