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PubMed2002

Neural marker genes differently expressed in subsets of embryonic neural cells of the ascidian Halocynthia roretzi.

Ascidians are lower chordates that possess a possible prototype of the vertebrate nervous system. The central and peripheral nervous systems of ascidian larvae are composed of only a few hundred cells (Nicol and Meinertzhagen, 1991). To investigate how these ascidian nervous systems develop, dissection at the molecular level using subset-specific markers is essential. Here we describe four new genes zygotically expressed in subsets of the ascidian neural cells. The spatial expression domains of these genes overlap in some parts but not in other parts of the nervous systems. Our results suggest that there are functionally different regions in the nervous systems owing to the gene expression differences. Further analyses of these genes will enable us to determine the molecular neuro-developmental characteristics of various clusters of neural cells.

Animals↗
PubMed2006

Definition and spatial annotation of the dynamic secretome during early kidney development.

The term "secretome" has been defined as a set of secreted proteins (Grimmond et al. [2003] Genome Res 13:1350-1359). The term "secreted protein" encompasses all proteins exported from the cell including growth factors, extracellular proteinases, morphogens, and extracellular matrix molecules. Defining the genes encoding secreted proteins that change in expression during organogenesis, the dynamic secretome, is likely to point to key drivers of morphogenesis. Such secreted proteins are involved in the reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) that occur during organogenesis of the metanephros. Some key metanephric secreted proteins have been identified, but many remain to be determined. In this study, microarray expression profiling of E10.5, E11.5, and E13.5 kidney and consensus bioinformatic analysis were used to define a dynamic secretome of early metanephric development. In situ hybridisation was used to confirm microarray results and clarify spatial expression patterns for these genes. Forty-one secreted factors were dynamically expressed between the E10.5 and E13.5 timeframe profiled, and 25 of these factors had not previously been implicated in kidney development. A text-based anatomical ontology was used to spatially annotate the expression pattern of these genes in cultured metanephric explants.

Animals↗
PubMed1998

Computer-generated three-dimensional reconstructions of serially sectioned mouse embryos.

We have been involved with a group of computer scientists and anatomists in the development of computer-based methodologies that not only combine the advantages of scanning electron microscopy and conventional histology, but provide the additional dimension of tissue recognition. The latter is achieved by the appropriate labelling of tissues and structures by delineation or 'painting'. Individually segmented anatomically defined tissues can be highlighted in a particular colour and viewed either in isolation or in combination with other appropriately labelled tissues and organs. Tissues can be shown in any orientation either as a transparent overlay on computer-generated histological sections or as 3-D images without the histological background. An additional feature of the system is that computer graphics technology combined with 3-D glasses now also allows the viewer to see the object under analysis in stereo. This facility has been found to be particularly helpful in drawing attention to topological relationships that had not previously been readily noted. As the mouse is now the mammalian model of choice in many areas of developmental research, it is of critical importance that a basic level of skill is available in the research community in the interpretation of serially sectioned material, for example, for the rapidly expanding field in which gene expression studies play a significant role. It is equally important that there is an understanding of the dynamic changes that occur in relation to the differentiation of the various organ systems seen in these early stages of development. What we emphasise here is the additional information that it is possible to gain from the use of this tool which, in our view, could not readily have been gained from the analysis of scanning electron micrographs or by studying conventional serial histological sections of similar stages of mouse embryonic development. The methodology has been developed as part of a large project to prepare a database of mouse developmental anatomy covering all stages from fertilisation to birth in order to allow the accurate spatial mapping of gene expression and cell lineage data onto the digital Atlas of normal mouse development. In this paper we show how this digital anatomical Atlas also represents a valuable teaching aid and research tool in anatomy.

Anatomy, Cross-Sectional↗
PubMed1999

Xenopus Pax-2/5/8 orthologues: novel insights into Pax gene evolution and identification of Pax-8 as the earliest marker for otic and pronephric cell lineages.

Pax genes are a family of transcription factors playing fundamental roles during organogenesis. We have recently demonstrated the expression of Pax-2 during Xenopus embryogenesis [Heller N, Brändli AW (1997): Mech Dev 69: 83-104]. Here we report the cloning and characterization of Xenopus Pax-5 and Pax-8, two orthologues of the Pax-2/5/8 gene family. Molecular phylogenetic analysis indicates that the amphibian Pax-2/5/8 genes are close relatives of their mammalian counterparts and that all vertebrate Pax-2/5/8 genes are derived from a single ancestral gene. Xenopus Pax-2/5/8 genes are expressed in spatially and temporally overlapping patterns during development of at least seven distinct tissues. Most strikingly, Xenopus Pax-8 was identified as the earliest marker of the prospective otic placode and of the intermediate mesoderm, indicating that Pax-8 may play a central role in auditory and excretory system development. Comparison of the expression patterns of fish, amphibian, and mammalian Pax-2/5/8 genes revealed that the tissue specificity of Pax-2/5/8 gene family expression is overall evolutionarily conserved. The expression domains of individual orthologues can however vary in a species-specific manner. For example, the thyroid glands of mammals express Pax-8, while in Xenopus Pax-2 is expressed instead. Our findings indicate that differential silencing of Pax-2/5/8 gene expression may have occurred after the different classes of vertebrates began to evolve separately.

Amino Acid Sequence↗
PubMed2005

Green fluorescent protein is a quantitative reporter of gene expression in individual eukaryotic cells.

Green fluorescent protein (GFP) has gained widespread use as a tool to visualize spatial and temporal patterns of gene expression in vivo. However, it is not generally accepted that GFP can also be used as a quantitative reporter of gene expression. We report that GFP is a reliable reporter of gene expression in individual eukaryotic cells when fluorescence is measured by flow cytometry. Two pieces of evidence support this conclusion: GFP fluorescence increases in direct proportion to the GFP gene copy number delivered to cells by a replication-defective adenovirus vector, Ad.CMV-GFP, and the intensity of GFP fluorescence is directly proportional to GFP mRNA abundance in cells. This conclusion is further supported by the fact that the induction of GFP gene expression from two inducible promoters (i.e., the TRE and ICP0 promoters) is readily detected by flow cytometric measurement of GFP fluorescent intensity. Collectively, the results presented herein indicate that GFP fluorescence is a reliable and quantitative reporter of underlying differences in gene expression.

Adenoviridae↗
PubMed2001

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Animals↗
PubMed1996

Analysis of WT1 gene expression during mouse nephrogenesis in organ culture.

The temporal and spatial expression patterns of the Wilms tumor gene, WT1, were studied during the organogenesis of the mouse kidney in vitro. In situ hybridization and immunocytochemistry localized cellular expression of WT1 in whole kidney organ cultures to the induced metanephric mesenchyme and developing podocytes. Organ cultures were further characterized immunocytochemically with antibodies that specifically labeled the different tubular epithelial components and supporting mesenchyme of the developing nephrons. In organ cultures, the WT1 expression pattern could be visualized in induced metanephric mesenchyme and entire cell cohorts of differentiating podocytes. Expression of WT1 and cell specific markers were retained in short-term monolayer cultures of dissociated kidneys. The development of the metanephric kidney in vitro involves a highly restricted temporal and spatial cellular expression pattern of WT1 which closely follows that observed in tissue sections from gestational kidney isolated during organogenesis in the mouse.

Animals↗
PubMed2002

Role of HuD and other RNA-binding proteins in neural development and plasticity.

Transcription factors have traditionally been viewed as the main determinants of gene expression. Yet, in recent years it has become apparent that RNA-binding proteins also play a critical role in determining the levels of expression of a large number of genes. Once mRNAs are transcribed, RNA-binding proteins can control all subsequent steps in their function, from alternative splicing and translation to mRNA transport and stability. In the nervous system, a large number of genes are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding proteins. This type of regulation is particularly important in the control of the temporal and spatial pattern of gene expression during neural development. This review will discuss the function of the embryonic lethal abnormal vision (ELAV)/Hu family of nervous system-specific RNA-binding proteins, with a special emphasis on HuD, a member of this family that controls GAP-43 mRNA stability and expression. In addition, we will present recent findings on other neural RNA-binding proteins: the ribonucleoprotein K homology (KH)-domain proteins, Fragile X mental retardation protein (FMRP), quakinguiable protein (QKI), and Nova-1. Together with the ELAV/Hu family, these proteins are essential for proper neural development and in some cases for plasticity in the mature brain. The biological significance of these proteins is evident not only by their evolutionary conservation but also by the magnitude of problems arising from autoimmune reactions against them or from mutations affecting their expression or function.

Aging↗
PubMed2000

LMX1B transactivation and expression in nail-patella syndrome.

Lmx1b, a member of the LIM homeodomain protein family, is essential for the specification of dorsal limb fates at the zeugopodal and autopodal level in vertebrates. We and others have shown that a skeletal dysplasia, nail-patella syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression. In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and nail dysplasia observed in NPS patients. Transfection studies showed that both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein, E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B and truncation mutations retained residual activity. These mutations fail to act in a dominant-negative manner on wild-type LMX1B in mixing studies, thereby supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.

Animals↗
PubMed1998

An internet-accessible database of mouse developmental anatomy based on a systematic nomenclature.

This paper reports an internet-accessible database of mouse developmental anatomy (DMDA) that currently holds a hierarchy of the names and synonyms of the tissues in the first 22 Theiler stages of development (E1-E13.5), together with other appropriate information. The purposes of the database are to provide, first, a nomenclature for analyzing normal and mutant mouse anatomy, and second a language for inputting, storing and querying gene-expression and other spatially organized data. DMDA currently contains some 6900 named and staged tissues (e.g. 360 and 1161 tissues in Theiler stage (TS) 14 (E9) and TS22 (E13.5) embryos). DMDA will be extended to include further lineage and other data when it becomes available. The database can be interactively accessed over the internet using either a Java or a non-Java WWW browser at http://genex.hgu.mrc.ac.uk/.

Animals↗
PubMed2006

Gene therapy progress and prospects--vectorology: design and production of expression cassettes in AAV vectors.

Adeno-associated virus (AAV) derived vectors are considered highly eligible vehicles for human gene therapy. Not only do they possess many great potential for clinical applications due to their wide range of tissue targets but also their excellent preclinical safety profile makes them particularly suitable candidates for treating serious diseases. Initial clinical trials have yielded encouraging results and prompted further improvements in their design and methods of production. Many studies have been performed to modify the tropism of recombinant (r)AAV by capsid modification. However, the precise control of spatial and temporal gene expression, which may be important in determining the safety and efficacy of gene transfer, lies in a rational choice and a subtle combination of various regulatory genetic elements to be inserted into the expression cassette. Moreover, new strategies based on such genetic sequences open new perspectives for enhancing vector genome persistence, disrupting or reducing pathogenic gene expression and even targeting genes.

Animals↗
PubMed1994

A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1.

Within the Hoxb homeobox gene complex, Hoxb-1 is the earliest member expressed in the mesoderm and neuroectoderm of primitive streak and presomite embryos, preceding rhombomere-restricted expression in the hindbrain. Ectopic exposure of embryos to retinoic acid alters spatial aspects of Hox gene expression patterns. However, the role of retinoids in regulating these genes during normal development is unclear. We have now identified two enhancers, 3' of the mouse Hoxb-1 gene, which together reconstruct the early endogenous expression pattern and mediate the early ectopic response to retinoic acid. Furthermore, these regions are functionally conserved in both chicken and pufferfish (Fugu rubripes) Hoxb-1 genes. The enhancer that controls the retinoic acid response, and regulates expression predominantly in neuroectoderm, contains a retinoic acid response element (RARE). Point mutations in the RARE abolish expression in neuroectoderm. Therefore, this RARE is not only involved in the ectopic response to retinoic acid, but is also essential for establishing aspects of the early Hoxb-1 expression pattern.

Animals↗
PubMed1992

Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo.

Exogenous retinoic acid (RA) has teratogenic effects on vertebrate embryos and alters Hox-C gene expression in vivo and in vitro. We wish to examine whether RA has a role in the normal regulation of Hox-C genes, and whether altered Hox-C gene expression in response to RA leads to abnormal morphology. The expression of 3' Hox-2 genes (Hox-2.9, Hox-2.8, Hox-2.6 and Hox-2.1) and a 5' gene (Hox-2.5) were examined by whole-mount in situ hybridization on embryos 4 hours after maternal administration of teratogenic doses of RA on embryonic day 7 to 9. The expression of the 3' Hox-2 genes was found to be ectopically induced in anterior regions in a stage-specific manner. The Hox-2.9 and Hox-2.8 genes were induced anteriorly in the neurectoderm in response to RA on day 7 but not at later stages. Expression of Hox-2.6 and Hox-2.1 was ectopically induced anteriorly in neurectoderm in response to RA on day 8. Hox-2.1 remained responsive on day 9, whereas Hox-2.6 was no longer responsive at this stage. The expression of the 5' gene Hox-2.5 was not detectably altered at any of these stages by RA treatments. We also examined the response of other genes whose expression is spatially regulated in early embryos. The expression of En-2 and Wnt-7b was not detectably altered by RA, whereas RAR beta expression was induced anteriorly by RA on day 7 and 8. Krox-20 expression was reduced in a stage- and region-specific manner by RA. The ectopic anterior expression of Hox-2.8 and Hox-2.9 induced by RA on day 7 was persistent to day 8, as was the altered expression of Krox-20. The altered pattern of expression of these genes in response to RA treatment on day 7 may be indicative of a transformation of anterior hindbrain to posterior hindbrain, specifically, a transformation of rhombomeres 1 to 3 towards rhombomere 4 identity with an anterior expansion of rhombomere 5. The ectopic expression of the 3' Hox-2 genes in response to RA is consistent with a role for these genes in mediating the teratogenic effects of RA; the rapid response of the Hox-C genes to RA is consistent with a role for endogenous RA in refining 3' Hox-C gene expression boundaries early in development.

Animals↗
PubMed2001

Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways.

Cholecystokinin (CCK) is a neuropeptide expressed in the small intestine and in the central and peripheral nervous system. CCK gene expression is both spatially and temporally regulated. In neurons CCK production is increased by growth factors, cyclic adenosine 3', 5'-monophosphate (cAMP), dopamine, estrogen, and injury situations, while intestinal CCK expression is mainly regulated by food intake. The function of the proximal CCK promoter has been examined by transfection of human CCK-CAT reporter constructs in cultured cells, DNase I footprinting and gel shift assays. These studies have led to the identification of regulatory elements and transcription factors important for basal and stimulated gene expression and depicted the signaling pathways involved in growth factor and cAMP induced CCK transcription. The review outlines the current knowledge of the regulation of CCK transcription and describes the role of putative transcription factors in tissue-specific CCK gene expression.

Animals↗
PubMed2005

Protein synthesis-dependent LTP in isolated dendrites of CA1 pyramidal cells.

Local dendritic protein synthesis provides a mechanism by which the effects of gene expression can be spatially restricted within synaptodendritic compartments of neurons. In the present study, we show that long-term potentiation (LTP), induced by two strong tetanic trains, can be produced in isolated CA1 apical dendrites and that new protein synthesis is critical for this dendritic LTP. LTP in isolated dendrites is also blocked by rapamycin, an inhibitor of growth-related protein synthesis, similar to that observed for LTP in the intact hippocampal slice. These results show that increased dendritic translation of proteins is a critical molecular mechanism for hippocampal LTP.

Animals↗
PubMed2006

Gene expression in cortex and hippocampus during acute pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis is associated with high mortality (approximately 30%) and morbidity. Up to 50% of survivors are affected by neurological sequelae due to a wide spectrum of brain injury mainly affecting the cortex and hippocampus. Despite this significant disease burden, the genetic program that regulates the host response leading to brain damage as a consequence of bacterial meningitis is largely unknown. We used an infant rat model of pneumococcal meningitis to assess gene expression profiles in cortex and hippocampus at 22 and 44 hours after infection and in controls at 22 h after mock-infection with saline. To analyze the biological significance of the data generated by Affymetrix DNA microarrays, a bioinformatics pipeline was used combining (i) a literature-profiling algorithm to cluster genes based on the vocabulary of abstracts indexed in MEDLINE (NCBI) and (ii) the self-organizing map (SOM), a clustering technique based on covariance in gene expression kinetics. RESULTS: Among 598 genes differentially regulated (change factor > or = 1.5; p < or = 0.05), 77% were automatically assigned to one of 11 functional groups with 94% accuracy. SOM disclosed six patterns of expression kinetics. Genes associated with growth control/neuroplasticity, signal transduction, cell death/survival, cytoskeleton, and immunity were generally upregulated. In contrast, genes related to neurotransmission and lipid metabolism were transiently downregulated on the whole. The majority of the genes associated with ionic homeostasis, neurotransmission, signal transduction and lipid metabolism were differentially regulated specifically in the hippocampus. Of the cell death/survival genes found to be continuously upregulated only in hippocampus, the majority are pro-apoptotic, while those continuously upregulated only in cortex are anti-apoptotic. CONCLUSION: Temporal and spatial analysis of gene expression in experimental pneumococcal meningitis identified potential targets for therapy.

Acute Disease↗
PubMed1994

DET1, a negative regulator of light-mediated development and gene expression in arabidopsis, encodes a novel nuclear-localized protein.

The mechanisms by which plants integrate light signals to modify endogenous developmental programs are largely unknown. One candidate for a signal transduction component that may integrate light with developmental pathways is the Arabidopsis DET1 gene product. Here we report the positional cloning of the DET1 locus and show that DET1 is a unique nuclear-localized protein. An analysis of a number of det1 mutants indicates that mutants with partial DET1 activity develop as light-grown plants in the dark. det1 null mutants share this phenotype, but also display severe defects in temporal and spatial regulation of gene expression. These results suggest that DET1 acts in the nucleus to control the cell type-specific expression of light-regulated promoters.

Amino Acid Sequence↗
PubMed1994

Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression.

The spatial patterns of IGF2 and H19 gene expression are strikingly similar during parts of human embryonic/fetal and early postnatal development. Notable exceptions were found with the ciliary anlage of the embryonic retina and the choroid plexus/leptomeninges, where transcripts from the IGF2 but not the H19 locus could be detected. Moreover, in contrast to the other tissue samples examined, the choroid plexus/leptomeninges expressed both parental IGF2 alleles. Whilst RNase protection analysis revealed a weak activity of the P1 promoter in the choroid plexus/leptomeninges, the P2, P3 and P4 promoters were all active wherever IGF2 was expressed. We discuss these observations with respect to a hypothesized coordinated control of the reciprocally imprinted and closely linked IGF2 and H19 loci.

Alleles↗