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At least 1,099 records · Page 61Linked to original sources
PubMed1999

Selective cloning of cell surface proteins involved in organ development: epithelial glycoprotein is involved in normal epithelial differentiation.

Coordinating the activities of neighboring cells during development in multicellular organisms requires complex cellular interactions involving secreted, cell surface, and extracellular matrix components. Although most cloning efforts have concentrated on secreted molecules, recent work has emphasized the importance of membrane-bound molecules during development. To identify developmental genes, we raised antibodies to normal embryonic pancreatic epithelial cell surface proteins. These antibodies were characterized and used to clone the genes coding for the proteins by a panning strategy. Using this approach, we cloned the rat homologue of the mouse epithelial glycoprotein (EGP). Our immunohistochemistry data, describing the expression of EGP during rat development, as well as our in vitro data, looking at the effect of the anti-EGP antibody and the extracellular domain of EGP on embryonic pancreatic epithelial cell number and volume, strongly suggest a role for EGP during pancreatic development.

Amino Acid Sequence↗
PubMed2004

Functional diversity of ventral midbrain dopamine and GABAergic neurons.

Recent findings indicate that VTA and SN dopaminergic (DA) and GABAergic neurons form subpopulations that are divergent in their electrophysiological features, vulnerability to neurodegeneration, and regulation by neuropeptides. This diversity can be correlated with the anatomical organization of the VTA and SN and their inputs and outputs. In this review we describe the heterogeneity in ion channels and firing patterns, especially burst firing, in subpopulations of dopamine neurons. We go on to describe variations in vulnerability to neurotoxic damage in models of Parkinson's disease in subgroups of DA neurons and its possible relationship to developmental gene regulation, the expression of different ion channels, and the expression of different protein markers, such as the neuroprotective marker calbindin. The electrophysiological properties of subgroups of GABAergic midbrain neurons, patterns of expression of protein markers and receptors, possible involvement of GABAergic neurons in a number of processes that are usually attributed exclusively to dopaminergic neurons, and the characteristics of a subgroup of neurons that contains both dopamine and GABA are also discussed.

Action Potentials↗
PubMed2007

FGFR3 is a negative regulator of the expansion of pancreatic epithelial cells.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are key signaling molecules for pancreas development. Although FGFR3 is a crucial developmental gene, acting as a negative regulator of bone formation, its participation remains unexplored in pancreatic organogenesis. We found that FGFR3 was expressed in the epithelia in both mouse embryonic and adult regenerating pancreata but was absent in normal adult islets. In FGFR3 knockout mice, we observed an increase in the proliferation of epithelial cells in neonates, leading to a marked increase in islet areas in adults. In vitro studies showed that FGF9 is a very potent ligand for FGFR3 and activates extracellular signal-related kinases (ERKs) in pancreatic cell lines. Moreover, FGFR3 blockade or FGFR3 deficiency led to increased proliferation of pancreatic epithelial cells in vivo. This was accompanied by an increase in the proportion of potential islet progenitor cells. Thus, our results show that FGFR3 signaling inhibits the expansion of the immature pancreatic epithelium. Consequently, this study suggests that FGFR3 participates in regulating pancreatic growth during the emergence of mature islet cells.

Aging↗
PubMed2006

Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin (Drm), a member of the cysteine knot family of bone morphogenetic protein (BMP) inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of gremlin in the lung interstitium of IPF patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of gremlin mRNA in lung biopsies from IPF patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from IPF patients also expressed elevated levels of gremlin, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of gremlin mRNA expression. In addition, A549 cells transfected to overexpress gremlin were more susceptible to transforming growth factor-beta-induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in IPF may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention.

Blotting, Northern↗
PubMed2006

Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon.

The NF-kappaB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-kappaB activity is mainly regulated through the phosphorylation of IkappaB by the IkappaB kinase (IKK) complex IKKalphabetagamma, leading to proteasome-mediated degradation of IkappaB, nuclear translocation of NF-kappaB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-kappaB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase (TBK)1 and IKKepsilon, are also thought to play a role in NF-kappaB regulation, but their functions remain unclear. TBK1 and IKKepsilon were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKepsilon and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKepsilon directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IkappaB/IKK pathway. IkappaBalpha degradation is not affected, but rather IKKepsilon-mediated phosphorylation of cRel leads to dissociation of the IkappaBalpha-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKepsilon/TBK1 phosphorylation.

Amino Acid Sequence↗
PubMed2000

A short history of MADS-box genes in plants.

Evolutionary developmental genetics (evodevotics) is a novel scientific endeavor which assumes that changes in developmental control genes are a major aspect of evolutionary changes in morphology. Understanding the phylogeny of developmental control genes may thus help us to understand the evolution of plant and animal form. The principles of evodevotics are exemplified by outlining the role of MADS-box genes in the evolution of plant reproductive structures. In extant eudicotyledonous flowering plants, MADS-box genes act as homeotic selector genes determining floral organ identity and as floral meristem identity genes. By reviewing current knowledge about MADS-box genes in ferns, gymnosperms and different types of angiosperms, we demonstrate that the phylogeny of MADS-box genes was strongly correlated with the origin and evolution of plant reproductive structures such as ovules and flowers. It seems likely, therefore, that changes in MADS-box gene structure, expression and function have been a major cause for innovations in reproductive development during land plant evolution, such as seed, flower and fruit formation.

Animals↗
PubMed2000

Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury).

The human T developmental gene has been implicated in the etiology of neural tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We have investigated the frequency of the T allelic variant TIVS7-2 in 218 Irish NTD case-parent triads. This population showed the same trend as previously reported, with an excess of the TIVS7-2 allele among cases. Log-linear modeling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mothers (RR = 0.91). The TIVS7-2 allele is markedly associated with cases born before 1980 (RR = 2.09; CI = 1.23-3.55; corrected p = 0.030), but not with more recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show any increased tendency to be homozygous for the thermolabile variant of the folate-dependent enzyme 5,10-methylene tetrahydrofolate reductase, which is an established genetic risk factor for NTDs. Since the incidence of NTDs has declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk factor(s), the impact of which have been diminishing over time.

Adolescent↗
PubMed2000

[Early events in the development of the nervous system].

In the recent years, real advances have been made in our understanding of some aspects of early neural development. A remarkable finding is the identification of neural inducers, the existence of which had been predicted by Mangold and Spemann almost seventy years ago. Another recent and important discovery consists in the identification of several developmental genes and growth factors. Indeed these two classes of molecules participate in the induction and in the physiological and morphological compartmentalization of the nervous system along its anteroposterior and dorsoventral axes.

Brain↗
PubMed2002

O-glycosylation of the nuclear forms of Pax-6 products in quail neuroretina cells.

Many transcription factors are demonstrated as being glycosylated with O-N-acetylglucosamine (GlcNAc) residue in transfected insect cell lines, but rarely in the original cells. For the first time, we demonstrate the O-GlcNAc modification of the p48/p46 Pax-6 gene (a developmental control gene involved in the eye morphogenesis) products in the quail neuroretina (QNR). In conjunction with a systematic PNGase F treatment, we used wheat germ agglutinin (WGA) binding, in vitro labeling with bovine galactosyltransferase, and labeling of cultured QNR with [14C]GlcNH2. Glycosylated forms of Pax-6 proteins were found in the nucleus of the neuroretina cells. WGA-selected Pax-6 proteins produced in the reticulocyte lysate were able to bind a DNA target, as well as to the unglycosylated form. The O-GlcNAc may, however, modulate protein interactions, mainly with other factors involved in the transcription process. Characterization of products released after reductive alkaline treatment of the proteins clearly demonstrates that N-acetylglucosamine is directly linked to serine or threonine residues. Examination of Pax-6 primary sequence allowed us to determine potential O-GlcNAc attachment sites. Most of these expected glycosylation sites appear to be located on the two DNA binding domains and on the carboxyterminal transactivation domain, while experimental evidence taken from WGA-selected proteins experiment points in favor of a main localization on the paired-box domain.

Acetylglucosamine↗
PubMed2002

Ankyrins, multifunctional proteins involved in many cellular pathways.

Ankyrins, originally discovered as components of the erythrocyte membrane appeared to be a family of animal proteins encoded in mammalian cells by three related genes. Developmentally regulated, tissue specific posttranscriptional processing generates a great variety of isoforms which seem to play specific role in various cells and subcellular structures, being involved, for example, in membrane skeleton organisation, ionic transport, maintenance of cell polarity as well as cell-cell adhesion regulation. The interaction between the membrane skeleton and cytoplasmic domains of transmembrane proteins plays a fundamental role in membrane integrity and stability as well as in many cellular processes. Once the cDNA sequence of red blood cell ankyrin was determined it became clear that "ankyrin-repeat" motifs are present in many proteins whose function is rather unrelated to the membrane skeleton, e.g. transcription factors. Ankyrins are a multigene family of intracellular, structural proteins that link several integral membrane proteins and the spectrin-based membrane cytoskeleton. The anion exchanger, Na+-K+ ATPase, a voltage dependent Na+ channel, an Na+/Ca2+-exchanger, and adhesion molecules have been reported to interact with ankyrin in nonerythroid cells. Ankyrin was first found to link integral membrane proteins to the underlying spectrin-actin based membrane skeleton in the human erythrocyte. It was subsequently described in a variety of vertebrate cells and tissues, including brain, epithelia, and skeletal muscle. Variable cellular localisation of these membrane proteins may be possible due to different relative affinities of various isoforms of ankyrin for target proteins.

Alternative Splicing↗
PubMed1992

Human congenital anomalies: application of new genetic tools and concepts.

The discovery of nontraditional inheritance and of developmental gene families common to all metazoans has revolutionized research on human congenital anomalies. The most gratifying results of these new concepts are summarized in Table 5: several human syndromes have already been related to their causative genes. Classic embryonic mechanisms (ie, gastrulation, segmentation, adhesion) also have been correlated with specific molecules. Perhaps most optimistic are the facts that many of the relevant molecules can be viewed as growth factors and that many anomalies are examples of extended or arrested development known as heterochrony. The implication is that genetic screening and preconceptional diagnosis will allow treatment of congenital malformations by supplementation/suppression of the maternofetal unit. This future specialty of "gestational endocrinology" is already being used for embryonic therapy of 21-hydroxylase deficiency.

Alleles↗
PubMed2005

Nuclear cloning, epigenetic reprogramming and cellular differentiation.

The full-term development of sheep, cows, goats, pigs and mice has been achieved through the transfer of somatic cell nuclei into enucleated oocytes. Despite these successes, mammalian cloning remains an inefficient process, with a preponderance of reconstructed embryos failing at early- to mid-gestation stages of development. The small percentage of conceptuses that survive to term are characterized by a high mortality rate and frequently display grossly increased placental and birth weights. It is likely that inappropriate expression of key developmental genes may contribute to lethality of cloned embryos. One of the most interesting issues of nuclear cloning is the question of genomic reprogramming, i.e. whether successful cloning requires the resetting of epigenetic modifications which are characteristic of the adult donor nucleus. Processes such as X-inactivation and genomic imprinting are known to depend on epigenetic modifications of the genome. The classical nuclear transfer experiments with frogs have suggested that the source of the donor nucleus affects the phenotype of the clone. We have, using expression profiling, compared gene expression in clones derived from embryonic stem (ES) cells and from somatic donor cell nuclei and find substantial gene dysregulation. Our results suggest that faulty reprogramming is caused by the nuclear cloning procedure itself. In addition, the type of donor nucleus contributes to the abnormal expression pattern seen in cloned animals. One of the major unresolved issues has been whether nuclei of terminally differentiated cells can be reprogrammed by transfer into the oocyte. To address this question we have derived monoclonal mice from B and T cells and used the genetic rearrangements of the immunoglobulin and T cell receptor genes to retrospectively verify the differentiation state of the donor nucleus. Finally, we discuss our recent studies on the reprogramming of nuclei from terminally differentiated neurons and from cancer cells.

Animals↗
PubMed1994

Fetal isoform of human retinoic acid receptor beta expressed in small cell lung cancer lines.

The retinoic acid receptor type beta (RAR beta) complementary DNA from a small cell tumor line was amplified, sequenced, and found to be homologous to the murine RAR beta 1. Seventeen lung tumor lines were analyzed. Five of seven small cell lung carcinoma lines expressed RAR beta 1, but only one other line (epidermoid) expressed the isoform, and this was at trace levels. Two other epidermoid lines, as well as three adenocarcinoma, two adenosquamous, and two large cell-derived lines did not express RAR beta 1. Nine adult human tissues, including lung, were analyzed, and in contrast to what has been reported for the mouse, undetectable or barely detectable levels were observed. On the other hand, a total of 13 different fetal tissues, at three different developmental stages, all expressed RAR beta 1. RAR beta 1 may be a master developmental gene in humans, and the remarkably specific association with small cell lung carcinoma suggests a molecular link between this type of cancer and development.

Amino Acid Sequence↗
PubMed1996

[Folate deficiency, cancer and congenital abnormalities. Is there a connection?].

The biochemical role of folate is in the interconversion of one-carbon units in intermediary metabolism; a process in which a methyl group is formed de novo. The methyl group is subsequently transferred to adenosylmethionine, which is an important methyl donor in the methylation of DNA. A negative correlation exists between the intake of folate in pregnancy and the occurrence of neural tube defects and certain malignant brain tumours in children. Numerous clinical studies have pointed to an association between folate status in adults and both the occurrence of cancer and the premalignant changes, cervical dysplasia, bronchial metaplasia, and colorectal adenomas. Folate deficiency may cause chromosomal damage, due to impaired DNA synthesis or repair. Moreover, decreased production of adenosylmethionine may influence the expression of developmental genes and of oncogenes and/or tumour suppressor genes through disturbed methylation of DNA.

Adult↗
PubMed1997

Thyroid hormone receptors in perennibranchiate amphibians.

Thyroid hormone has long been known to induce metamorphosis in amphibians. The understanding of the molecular steps controlling the completion of metamorphosis has nevertheless been hampered by the complexity of this event. The comparison of organisms in which metamorphosis does or does not occur, may provide clues into the molecular cascade that control it. Up to now the available data suggest that perennibranchiate amphibians retain their larval characters mainly because their tissues do not respond to thyroid hormones. In such a context the recent identification of a thyroid hormone receptor alpha in the perennibranchiate Proteus anguinus is provocative (Ho Huynh et al., Int. J. Dev. Biol. 40:537-543, 1996). In the present paper, we provide evidences that this recently described sequence is in fact a sequence from Xenopus laevis. Indeed, we identified the authentic thyroid hormone receptors of both alpha and beta types in two perennibranchiate species Necturus maculosus and Proteus anguinus. The various controls required to ascertain the authenticity of a developmental gene cloned by PCR or RT-PCR analysis are presented. The results reported in the present paper are relevant with phylogenetical analysis. This induces our team to conclude that the Proteus TR alpha sequence reported by Ho Huynh et al. (1996) reflects a contamination of the RT-PCR by Xenopus laevis material.

Amphibians↗
PubMed1998

22q11 deletion syndrome in adults with schizophrenia.

Genetic syndromes associated with deletions at chromosome 22q11 generally have been diagnosed during childhood based on a constellation of physical features. To investigate a reported association of velocardiofacial syndrome with psychotic disorders in adults, we assessed subjects with DSM-IV schizophrenia or schizoaffective disorder who were referred with two or more syndromal features (palatal, cardiac, facial, or other congenital anomalies, and/or learning difficulties). We report on 10 subjects (5 men and 5 women), mean age 27.2 (SD 6.0) years, who were found to have a 22q11 deletion at locus D22S75 using fluorescence in-situ hybridization (FISH). The mean age at onset of psychosis was 19.6 (SD 4.6) years. Symptoms and course of the psychotic illnesses were unremarkable, but additional signs such as temper outbursts were common. These adult subjects had significantly fewer major palatal (P = .0001) and conotruncal cardiac (P = .05) anomalies but the same high rate of learning difficulties as a sample with deletion 22q11 ascertained through a pediatric clinic [Lindsay et al. (1995): Am J Med Genet 57:514-522]. Minor congenital features and rate of transmitted cases were similar to those previously reported. These results replicate the association of a 22q11 deletion syndrome with schizophrenia and confirm the importance of ascertainment in influencing the phenotype found. The findings support a developmental gene in the 22q11 deletion region causing a complex phenotype which may include significant behavioral components that emerge over time. We support using the term "22q11 deletion syndrome (22DS)," which would encompass physical and psychiatric features, and could also be applied to describe a genetic subtype of schizophrenia.

Abnormalities, Multiple↗
PubMed1997

[Human cervico-facial morphogenesis. Evaluation of acquired data and current outlook. Second part: cervical morphogenesis].

After having recalled the formation of the so-called "branchial" organisation, each component of the segmentary units constituting this organisation is analysed, as well as their particularities. This lead us to recognize the existence of only five branchial arches in the human embryo, without an intermediary arch between the fourth arch and the pulmonary arch. This question is moreover linked to the signification of the so-called "ultimobranchial" body, which must be connected with the fourth pharyngeal pouch. The question of cervical segmentation is inseparable from the question of cephalic metamerisation. Two segments are individualised in front of the mandibular process: the fronto-nasal process and the maxillary process, corresponding to premandibular arches, which existence is well established in paleontology. In addition to the peripheral expression of this cervico-cephalic segmentation marqued by primitive characters. We observe the paraxial expression of segmentation by the somitomeres and the somites. Recent data provided by the developmental genes confirm that only one process is at the origin of these two expressions which appear distinct, but lead to a unitary organisation. The mutation of the gene Pax 6 affecting in the same time the nasal placode and the optic vesicle confirms the unity of the fronto-nasal process. The pre-eminence of genetic expression on skeletal, muscular and nervous tissues with respect to the vascular system confirms the inadequacy of the criterion given by the aortic arches for the analysis of the cervico-cephalic development, although it is classically linked to the concept of an embryonic "branchial apparatus".

Biological Evolution↗
PubMed1998

[Histogenesis of the corpus callosum].

The corpus callosum results from neocortical commissural axon fasciculation. Its development reflects the interhemispheric circuitry and then follows the successive steps of synaptogenesis. The first stage consists of callosal neuron differentiation, which allows the extention of the future callosal axon; this is an early event that occurs while neuronal migration to the cortical plate is still ongoing. Callosal axon guidance towards its specific target is the second step which includes reaching and crossing the midline and further target recognition with formation of initial synapses. This period extends from 12 to 22 post-conceptional weeks and corresponds to the following histological features: i) progressive invasion by callosal growth cones of the dorsal part of lamina reuniens through a preformed glial pathway; ii) appearence of the three parts of corpus callosum, namely truncus, rostrum and lastly the splenium. Both these stages are genetically controlled either directly by developmental gene expression (neurogenesis genes) or indirectly by the establishment of cue maps (spatial expression of extra-cellular matrix proteins). The third step is that of synapse remodeling by synaptic activity, giving rise to axonal elimination, macroscopically revealed by a transitory thinning of corpus callosum. This perinatal event contributes to the corpus callosum acquiring a mature topography. Finally, analysis of corpus callosum ontogenesis appears as a striking model of synaptogenesis study and provides physiopathological assumptions for a understanding of the corpus callosum agenesis.

Animals↗