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Peter Gruss - One of the best experts on this subject based on the ideXlab platform.

  • Pax Genes and the differentiation of hormone-producing endocrine cells in the pancreas
    Mechanisms of Development, 2000
    Co-Authors: Cord E. Dohrmann, Peter Gruss, Lydia Lemaire
    Abstract:

    Despite the pivotal role of the pancreas in hormonally-regulated pathways in the body, e.g. glucose homeostasis, the genetic mechanisms defining it have for many years remained largely enigmatic. After years out of the spotlight, pancreas development has once again come to centre stage. To a large extent, this is due to recent advances made through the detailed analysis of transgenic mice which have been engineered to carry mutations in specific developmental control Genes. This review specifically focuses on the specification of the endocrine pancreas lineage and in particular on the role of the developmental control Genes Pax4 and Pax6 in the generation of specific endocrine cell types. The comparison of various phenotypes of different mouse mutants affecting endocrine development supports a model in which Pax4 and Pax6 are required for the differentiation of certain endocrine cell lineages and implies a potential for acting at different levels of endocrine development.

  • role of Pax Genes in endoderm derived organs
    Trends in Endocrinology and Metabolism, 1999
    Co-Authors: Ahmed Mansouri, Luc Stonge, Peter Gruss
    Abstract:

    Pax Genes, which encode a family of transcription factors, are essentially required for the formation of several tissues from all germ layers in the mammalian embryo. Specifically, in organoGenesis, they are involved in triggering early events of cell differentiation. The differentiation of endoderm-derived endocrine pancreas is mediated through Pax4 and Pax6. In the thyroid gland, Pax8 is essential for the formation of thyroxine-producing follicular cells, also of endodermal origin. The analysis of loss-of-function mutants revealed a common function of Pax Genes in organoGenesis.

  • Pax Genes and Their Role in OrganoGenesis
    Cancer Research, 1999
    Co-Authors: Ahmed Mansouri, Guy Goudreau, Peter Gruss
    Abstract:

    Pax Genes have been cloned on the basis of their homology to the Drosophila segmentation gene paired. They share a common domain, the paired domain, that is sufficient to mediate sequence-specific DNA binding. Thus far, nine members have been characterized, which exhibit highly restricted temporal and spatial expression patterns. The analysis of mouse mutants has revealed their crucial role in the formation of a variety of tissues. In particular, they are involved in the regulation of early steps in organ development. They act to define the regional specification of distinct germ layers.

  • Pax Genes and their role in organoGenesis. Discussion
    Cancer Research, 1999
    Co-Authors: Ahmed Mansouri, Peter Gruss, Guy Goudreau, P. Sharp, M. Busslinger
    Abstract:

    Pax Genes have been cloned on the basis of their homology to the Drosophila segmentation gene paired. They share a common domain, the paired domain, that is sufficient to mediate sequence-specific DNA binding. Thus far, nine members have been characterized, which exhibit highly restricted temporal and spatial expression patterns. The analysis of mouse mutants has revealed their crucial role in the formation of a variety of tissues. In particular, they are involved in the regulation of early steps in organ development. They act to define the regional specification of distinct germ layers.

  • Pax6 is required for differentiation of glucagon producing alpha cells in mouse pancreas
    Nature, 1997
    Co-Authors: Luc Stonge, Ahmed Mansouri, Beatriz Sosapineda, Kamal Chowdhury, Peter Gruss
    Abstract:

    The functional unit of the endocrine pancreas is the islet of Langerhans. Islets are nested within the exocrine tissue of the pancreas and are composed of alpha-, beta-, delta- and gamma-cells. beta-Cells produce insulin and form the core of the islet, whereas alpha-, delta- and gamma-cells are arranged at the periphery of the islet and secrete glucagon, somatostatin and a pancreatic polypeptide, respectively. Little is known about the molecular and genetic factors regulating the lineage of the different endocrine cells. Pancreas development is known to be abolished in Pdx1-mutant mice and Pax4 mutants lack insulin-producing beta-cells. Here we show that the paired-box gene Pax6 is expressed during the early stages of pancreatic development and in mature endocrine cells. The pancreas of Pax6 homozygous mutant mice lack glucagon-producing cells, suggesting that Pax6 is essential for the differentiation of alpha-cells. As mice lacking Pax4 and Pax6 fail to develop any mature endocrine cells, we conclude that both Pax Genes are required for endocrine fate in the pancreas.

Zbynek Kozmik - One of the best experts on this subject based on the ideXlab platform.

  • the role of Pax Genes in eye evolution
    Brain Research Bulletin, 2008
    Co-Authors: Zbynek Kozmik
    Abstract:

    Anatomically widely different designs of animal eyes have long been thought to arise independently multiple times during evolution. This morphology-based view has been challenged by the identification of a highly conserved transcription factor Pax6 that plays a key role in eye development in both flies and mammals. The origin of Pax Genes predates the origin of eyes and the nervous system since a PaxB-like gene, belonging to the Pax2/5/8 gene subfamily, was identified in sponge lacking nervous system. Structurally similar PaxB gene is implicated in visual system development in jellyfish, the most basal organism possessing complex eyes. The widespread use of Pax Genes in the genetic program underlying eye formation throughout the animal kingdom raises a question why certain transcription factors have been frequently redeployed to build eyes. A model is proposed that provides a plausible explanation for the apparently ancient role of Pax Genes in eye evolution.

  • Pax Genes in eye development and evolution
    Current Opinion in Genetics & Development, 2005
    Co-Authors: Zbynek Kozmik
    Abstract:

    Animal eyes with widely different anatomical designs have long been thought to arise independently, multiple times during evolution. This view was challenged about a decade ago by the landmark discoveries that Pax6, a highly conserved transcription factor, plays a key role in eye morphoGenesis in both flies and mammals. Since then, more evidence has emerged in favour of the redeployment of Pax6 and some other developmental control Genes within the genetic program underlying eye formation throughout the animal kingdom. Recent work has indicated that other members of the Pax gene family play a pivotal role in eye morphoGenesis. The Eye gone gene regulates eye growth in Drosophila, whereas the PaxB gene is implicated in visual system development in jellyfish, the most basal organism possessing eyes.

  • role of Pax Genes in eye evolution a cnidarian Paxb gene uniting Pax2 and Pax6 functions
    Developmental Cell, 2003
    Co-Authors: Zbynek Kozmik, Michael Daube, Erich Frei, Markus Noll, Barbara Norman, Larry J Dishaw, Joram Piatigorsky
    Abstract:

    Abstract PaxB from Tripedalia cystophora , a cubomedusan jellyfish possessing complex eyes (ocelli), was characterized. PaxB , the only Pax gene found in this cnidarian, is expressed in the larva, retina, lens, and statocyst. PaxB contains a Pax2/5/8-type paired domain and octapeptide, but a Pax6 prd -type homeodomain. Pax2/5/8-like properties of PaxB include a DNA binding specificity of the paired domain, activation and inhibitory domains, and the ability to rescue spa pol , a Drosophila Pax2 eye mutant. Like Pax6, PaxB activates jellyfish crystallin and Drosophila rhodopsin rh6 promoters and induces small ectopic eyes in Drosophila . Pax6 has been considered a "master" control gene for eye development. Our data suggest that the ancestor of jellyfish PaxB, a PaxB-like protein, was the primordial Pax protein in eye evolution and that Pax6-like Genes evolved in triploblasts after separation from Cnidaria, raising the possibility that cnidarian and sophisticated triploblastic eyes arose independently.

  • overexpression of Pax5 is not sufficient for neoplastic transformation of mouse neuroectoderm
    International Journal of Cancer, 2001
    Co-Authors: Joachim P Steinbach, Zbynek Kozmik, Peter L Pfeffer, Adriano Aguzzi
    Abstract:

    The developmental control Genes of the Pax family are essential for brain development. Several Pax Genes are also involved in chromosomal translocations causing malignancies in humans, and Pax5 expression is deregulated in medulloblastomas. We have investigated whether Pax5 can induce tumors in the developing mouse brain. Primary mouse embryonic neuroectodermal cells were retrovirally transduced with mouse Pax5 and transplanted into the brain of syngeneic host mice. No tumors developed in 36 transplants after one year, and there were no alterations in the differentiation pattern of the neural transplants. We then generated transgenic mice expressing human Pax5 under control of the Engrailed-2 promoter, which is expressed in the cerebellar external granule cell layer and in medulloblastomas. Sustained expression was achieved in the cerebellum of transgenic animals throughout lifetime. Expression levels were similar to those observed in human medulloblastomas. Again, cerebellar morphoGenesis was undisturbed, and no tumors arose. These results strongly argue against a dominant transforming activity of Pax5 in NEC and in cerebellar granule cell precursors of mice, and underline the restricted tissue-specificity of Pax5 related oncoGenesis.

  • independent regulation of the two Pax5 alleles during b cell development
    Nature Genetics, 1999
    Co-Authors: Stephen L Nutt, Zbynek Kozmik, Andreas Weith, Susanne Vambrie, Peter Steinlein, Antonius Rolink, Meinrad Busslinger
    Abstract:

    The developmental control Genes of the Pax family are frequently associated with mouse mutants and human disease syndromes1,2,3. The function of these transcription factors is sensitive to gene dosage, as mutation of one allele1,2,3 or a modest increase in gene number4 results in phenotypic abnormalities. Pax5 has an important role in B-cell and midbrain development5,6,7. By following the expression of individual Pax5 alleles at the single-cell level, we demonstrate here that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only one allele in early progenitors and mature B cells, whereas it switches to a biallelic transcription mode in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, independent of parental origin and correlates with synchronous replication, in contrast with imprinted8,9 and other monoallelically expressed Genes10,11. As a consequence, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of one allele in heterozygous mice results in deletion of the cell population expressing the mutant allele due to loss of Pax5 function at the single-cell level. Similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other Pax Genes with human disease.

Meinrad Busslinger - One of the best experts on this subject based on the ideXlab platform.

  • Pax Genes evolution and function
    eLS, 2006
    Co-Authors: Maxime Bouchard, Alexander Schleiffer, Frank Eisenhaber, Meinrad Busslinger
    Abstract:

    The transcription factors of the Pax protein family have been conserved throughout metazoan evolution and play essential roles in brain development and organoGenesis. Loss-of-function and gain-of-function mutations in Pax Genes cause inherited disease syndromes and tumor formation respectively. Keywords: Pax; transcription factor; paired domain; gene duplications; brain development; organoGenesis; haploinsufficiency; inherited disease; tumoriGenesis

  • monoallelic expression of Pax5 a paradigm for the haploinsufficiency of mammalian Pax Genes
    Biological Chemistry, 1999
    Co-Authors: Stephen L Nutt, Meinrad Busslinger
    Abstract:

    It is generally assumed that most mammalian Genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a loss-of-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the 'default' state. However, a minority of Genes are semi-dominant, as heterozygous loss-of-function mutation in these Genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian Pax Genes, which are associated with mouse developmental mutants and human disease syndromes. Recently we have reported that the Pax5 gene is subject to allele-specific regulation during B cell development. Pax5 is predominantly transcribed from only one of its two alleles in early B-lymphoid progenitors and mature B cells, while it transiently switches to a biallelic mode of transcription in pre-B and immature B cells. As a consequence, B-lymphoid tissues are mosaic with regard to the transcribed allele, and heterozygous mutation of Pax5 therefore results in deletion of B lymphocytes expressing only the mutant allele. The allele-specific regulation of Pax5 raises the intriguing possibility that monoallelic expression may also be the mechanism causing the haploinsufficiency of other Pax Genes. In this review, we discuss different models accounting for the haploinsufficiency of mammalian Pax Genes, provide further evidence in support of the allele-specific regulation of Pax5 and discuss the implication of these findings in the context of the recent literature describing the stochastic and monoallelic activation of other hematopoietic Genes.

  • independent regulation of the two Pax5 alleles during b cell development
    Nature Genetics, 1999
    Co-Authors: Stephen L Nutt, Zbynek Kozmik, Andreas Weith, Susanne Vambrie, Peter Steinlein, Antonius Rolink, Meinrad Busslinger
    Abstract:

    The developmental control Genes of the Pax family are frequently associated with mouse mutants and human disease syndromes1,2,3. The function of these transcription factors is sensitive to gene dosage, as mutation of one allele1,2,3 or a modest increase in gene number4 results in phenotypic abnormalities. Pax5 has an important role in B-cell and midbrain development5,6,7. By following the expression of individual Pax5 alleles at the single-cell level, we demonstrate here that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only one allele in early progenitors and mature B cells, whereas it switches to a biallelic transcription mode in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, independent of parental origin and correlates with synchronous replication, in contrast with imprinted8,9 and other monoallelically expressed Genes10,11. As a consequence, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of one allele in heterozygous mice results in deletion of the cell population expressing the mutant allele due to loss of Pax5 function at the single-cell level. Similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other Pax Genes with human disease.

  • the characterization of novel Pax Genes of the sea urchin and drosophila reveal an ancient evolutionary origin of the Pax2 5 8 subfamily
    Mechanisms of Development, 1997
    Co-Authors: Thomas Czerny, Maxime Bouchard, Zbynek Kozmik, Meinrad Busslinger
    Abstract:

    The developmental control Genes of the Pax family can be grouped into different subclasses according to structure and sequence homology. Here we describe the isolation and characterization of three novel Pax Genes of the sea urchin for which no homologues are yet known in other animal phyla. One of these Genes, suPaxB, codes for the previously characterized transcription factor TSAP which is involved in the developmental regulation of two pairs of late histone Genes. Furthermore, conserved members of the Pax2/5/8 subfamily, which have so far been described only in vertebrates, were isolated not only from the sea urchin, but also from Drosophila and C. elegans. Hence, the Pax2/5/8 transcription factors constitute an ancient subfamily of highly conserved Pax proteins. During Drosophila embryoGenesis, the Pax258 gene is shown to be expressed in the precursor cells of the external sensory organs, thus suggesting a role for Pax258 in the early development of the peripheral nervous system of insects.

  • deregulated expression of Pax5 in medulloblastoma
    Proceedings of the National Academy of Sciences of the United States of America, 1995
    Co-Authors: Zbynek Kozmik, Meinrad Busslinger, Ulrich Sure, Daniela Ruedi, Adriano Aguzzi
    Abstract:

    Medulloblatoma is a pediatric brain tumor originating in the human cerebellum. A collection of 23 medulloblastomas was analyzed for expression of the developmental control Genes of the Pax and EN gene families by RNase protection and in situ hybridization. Of all nine Pax Genes investigated, only Pax5 and Pax6 were consistently expressed in most medulloblastomas (70 and 78% of all cases, respectively), as were the Genes EN1 (57%) and EN2 (78%). EN1, EN2, and Pax6 Genes were also expressed in normal cerebellar tissue, and their expression in medulloblastoma is consistent with the hypothesis that this tumor originates in the external granular layer of the developing cerebellum. Pax5 transcripts were, however, not detected in the neonatal cerebellum, indicating that this gene is deregulated in medulloblastoma. In the desmoplastic variant of medulloblastoma, Pax5 expression was restricted to the reticulin-producing proliferating tumor areas containing undifferentiated cells; Pax5 was not expressed in the reticulin-free nonproliferating islands undergoing neuronal differentiation. These data suggest that deregulated expression of Pax5 correlates positively with cell proliferation and inversely with neuronal differentiation in desmoplastic medulloblastoma.

Rudi Balling - One of the best experts on this subject based on the ideXlab platform.

  • Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities
    Genes & Development, 1998
    Co-Authors: Heiko Peters, Annette Neubuser, Klaus Kratochwil, Rudi Balling
    Abstract:

    Pax Genes have been shown to play important roles in mammalian development and organoGenesis. Pax9, a member of this transcription factor family, is expressed in somites, pharyngeal pouches, mesenchyme involved in craniofacial, tooth, and limb development, as well as other sites during mouse embryoGenesis. To analyze its function in vivo, we generated Pax9 deficient mice and show that Pax9 is essential for the development of a variety of organs and skeletal elements. Homozygous Pax9-mutant mice die shortly after birth, most likely as a consequence of a cleft secondary palate. They lack a thymus, parathyroid glands, and ultimobranchial bodies, organs which are derived from the pharyngeal pouches. In all limbs, a supernumerary preaxial digit is formed, but the flexor of the hindlimb toes is missing. Furthermore, craniofacial and visceral skeletoGenesis is disturbed, and all teeth are absent. In Pax9-deficient embryos tooth development is arrested at the bud stage. At this stage, Pax9 is required for the mesenchymal expression of Bmp4, Msx1, and Lef1, suggesting a role for Pax9 in the establishment of the inductive capacity of the tooth mesenchyme. In summary, our analysis shows that Pax9 is a key regulator during the development of a wide range of organ primordia.

  • Pax Genes and organoGenesis: Pax9 meets tooth development
    European Journal of Oral Sciences, 1998
    Co-Authors: Heiko Peters, Annette Neubuser, Rudi Balling
    Abstract:

    Pax Genes encode a family of transcription factors that play key roles during embryoGenesis. They are required for the development of a variety of organs including the nervous and muscular system, skeleton, eye, ear, kidney, thymus, and pancreas. Whereas the developmental roles of many of the nine known Pax Genes have been analyzed in great detail, a functional analysis of Pax9 has just begun. During mouse embryoGenesis, Pax9 exhibits a highly specific expression pattern in derivatives of the foregut endoderm, somites, limb mesenchyme, midbrain, and the cephalic neural crest. In the mandibular arch mesenchyme, the expression of Pax9 marks the prospective sites of tooth development prior to any morphological signs of odontoGenesis and is maintained in the developing tooth mesenchyme thereafter. To understand the function of Pax9 during mouse embryoGenesis, we recently have created a null allele by gene targeting. Preliminary analyses show that Pax9 is essential for the formation of teeth, and we conclude that Pax9 is required for tooth development to proceed beyond the bud stage. Here, we briefly summarize our current knowledge about Pax Genes and introduce Pax9 to the growing family of factors which are involved in tooth development.

  • Pax Genes and organoGenesis
    BioEssays, 1997
    Co-Authors: Edgar Dahl, Haruhiko Koseki, Rudi Balling
    Abstract:

    Pax Genes are a family of development control Genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing Genes were detected in Drosophila malenogaster, where they exert multiple functions during embryoGenesis. In vertebrates, Pax Genes are also involved in embryoGenesis. Mutations in four out of nine characterized Pax Genes have been associated with either congenital human diseases such as Waardenburg syndrome (Pax3), Aniridia (Pax6), Peter's anomaly (Pax6), renal coloboma syndrome (Pax2), Small eye (Pax6), (Pax21Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate Pax Genes are key regulators during organoGenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax Genes are involved in pattern formation during embryoGenesis, possibly by determiing the time and place of organ initiation of morphoGenesis. For most tissues, however, the nature of the primary development action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position-specific regulation of cell proliferation.

  • Pax Genes and organoGenesis
    BioEssays, 1997
    Co-Authors: Edgar Dahl, Haruhiko Koseki, Rudi Balling
    Abstract:

    Pax Genes are a family of developmental control Genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing Genes were detected in Drosophila melanogaster, where they exert multiple functions during embryoGenesis. In vertebrates, Pax Genes are also involved in embryoGenesis. Mutations in four out of nine characterized Pax Genes have been associated with either congenital human diseases such as Waardenburg syndrome (Pax3), Aniridia (Pax6), Peter's anomaly (Pax6), renal coloboma syndrome (Pax2) or spontaneous mouse mutants (undulated (Pax1), Splotch (Pax3), Small eye (Pax6), Pax2(1)Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate Pax Genes are key regulators during organoGenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax Genes are involved in pattern formation during embryoGenesis, possibly by determining the time and place of organ initiation or morphoGenesis. For most tissues, however, the nature of the primary developmental action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position-specific regulation of cell proliferation.

  • Pax Genes and human neural tube defects an amino acid substitution in Pax1 in a patient with spina bifida
    Journal of Medical Genetics, 1996
    Co-Authors: F A Hol, Rudi Balling, M P A Geurds, Sansnee Chatkupt, Y Y Shugart, Constance T R M Schranderstumpel, William G Johnson, Ben C J Hamel, Edwin C M Mariman
    Abstract:

    From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the Pax gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of Pax1, Pax3, Pax7, and Pax9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the Pax1, Pax7, and Pax9 Genes and of the complete Pax3 gene. In one patient with spina bifida, a mutation in the Pax1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the Pax3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the Pax7 and Pax9 Genes. Our findings so far do not support a major role of the Pax Genes examined in the aetiology of NTD. However, the detection of a mutation in Pax1 suggests that, in principle, this gene can act as a risk factor for human NTD.

Gregory R. Dressler - One of the best experts on this subject based on the ideXlab platform.

  • the groucho associated phosphatase ppm1b displaces Pax transactivation domain interacting protein ptip to switch the transcription factor Pax2 from a transcriptional activator to a repressor
    Journal of Biological Chemistry, 2015
    Co-Authors: Saji Abraham, Gregory R. Dressler, Raghavendra Paknikar, Samina Bhumbra, Danny Luan, Rohan Garg, Sanjeevkumar R Patel
    Abstract:

    Pax Genes encode developmental regulatory proteins that specify cell lineages and tissues in metazoans. Upon binding to DNA through the conserved paired domain, Pax proteins can recruit both activating and repressing complexes that imprint distinct patterns of histone methylation associated with either gene activation or silencing. How the switch from Pax-mediated activation to repression is regulated remains poorly understood. In this report, we identify the phosphatase PPM1B as an essential component of the Groucho4 repressor complex that is recruited by Pax2 to chromatin. PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation. Loss of PPM1B prevents Groucho-mediated gene repression. Thus, PPM1B helps switch Pax2 from a transcriptional activator to a repressor protein. This can have profound implications for developmental regulation by Pax proteins and suggests a model for imprinting specific epigenetic marks depending on the availability of co-factors.

  • Patterning and early cell lineage decisions in the developing kidney: the role of Pax Genes
    Pediatric nephrology (Berlin Germany), 2011
    Co-Authors: Gregory R. Dressler
    Abstract:

    Specification of the intermediate mesoderm and the epithelial derivatives that will make the mammalian kidney depends on the concerted action of many transcription factors and signaling proteins. Among the earliest Genes expressed in the nephric duct and surrounding mesenchyme is Pax2, whose function is essential for making and maintaining the epithelium. The Pax2 protein is subject to phosphorylation in response to signals that activate the c-Jun N-terminal kinase pathway, including Wnts and BMPs. In cell culture systems, Pax2 is know to recruit components of a histone H3 lysine 4 methyltransferase complex to specific DNA sites to alter the pattern of histone modifications and determine gene expression. This epigenetic function may underlie the ability of Pax2 and similar proteins to maintain cell lineages during development.

  • Pax2 in development and renal disease
    The International Journal of Developmental Biology, 1999
    Co-Authors: Gregory R. Dressler, Adrian S Woolf
    Abstract:

    Pax Genes are associated with a variety of developmental mutations in mouse and man that are gene dosage sensitive, or haploinsufficient. The Pax2 gene encodes a DNA binding, transcription factor whose expression is essential for the development of the renal epithelium. Both gain and loss of function mutants in the mouse demonstrate a requirement for Pax2 in the conversion of metanephric mesenchymal precursor cells to the fully differentiated tubular epithelium of the nephron. However, Pax2 expression is down-regulated as cells leave the mitotic cycle. Humans carrying a single Pax2 mutant allele exhibit renal hypoplasia, vesicoureteric reflux, and optic nerve colobomas. Conversely, persistent expression of Pax2 has been demonstrated in a variety of cystic and dysplastic renal diseases and correlates with continued proliferation of renal epithelial cells. Thus, Pax2 misexpresssion may be a key determinant in the initiation and progression of renal diseases marked by increased or deregulated cell proliferation.

  • comparative analysis of Pax 2 protein distributions during neurulation in mice and zebrafish
    Mechanisms of Development, 1992
    Co-Authors: Andreas W Puschel, Monte Westerfield, Gregory R. Dressler
    Abstract:

    Abstract Members of different vertebrate species share a number of developmental mechanisms and control Genes, suggesting that they have similar genetic programs of development. We compared the expression patterns of the Pax-2 protein in Mus musculus and Brachydanio rerio to gain a better understanding of the evolution of developmental control Genes. We found that the tissue specificity and the course of Pax-2 expression relative to specific developmental processes are remarkably similar during the early development of the two organisms. The brain, the optic stalk, the auditory vesicle, the pronephros, and single cells in the spinal cord and the hindbrain express Pax-2 in both species. The Pax-2 expression domain in the prospective brain of E8 mouse embryos has no been described previously. Expression appears first during early neurulation at the junction between the midbrain and hindbrain. However, there are some differences in Pax-2 expression between the two species. Most notable, expression at the midbrain/hindbrain boundary is no longer dectable after E11 in the mouse. Using monoclonal antibodies, we could exclude that primary neurons express Pax-2 in the zebrafish spinal cord. Our results confirm that Pax Genes are highly conserved both in sequences and in expression patterns, indicating that they may have a function during early development that has been conserved during vertebrate evolution.

  • comparative analysis of Pax 2 protein distributions during neurulation in mice and zebrafish
    Mechanisms of Development, 1992
    Co-Authors: Andreas W Puschel, Monte Westerfield, Gregory R. Dressler
    Abstract:

    Members of different vertebrate species share a number of developmental mechanisms and control Genes, suggesting that they have similar genetic programs of development. We compared the expression patterns of the Pax-2 protein in Mus musculus and Brachydanio rerio to gain a better understanding of the evolution of developmental control Genes. We found that the tissue specificity and the time course of Pax-2 expression relative to specific developmental processes are remarkably similar during the early development of the two organisms. The brain, the optic stalk, the auditory vesicle, the pronephros, and single cells in the spinal cord and the hindbrain express Pax-2 in both species. The Pax-2 expression domain in the prospective brain of E8 mouse embryos has not been described previously. Expression appears first during early neurulation at the junction between the midbrain and hindbrain. However, there are some differences in Pax-2 expression between the two species. Most notable, expression at the midbrain/hindbrain boundary is no longer detectable after E11 in the mouse. Using monoclonal antibodies, we could exclude that primary neurons express Pax-2 in the zebrafish spinal cord. Our results confirm that Pax Genes are highly conserved both in sequences and in expression patterns, indicating that they may have a function during early development that has been conserved during vertebrate evolution.