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Michael Wegner - One of the best experts on this subject based on the ideXlab platform.

  • idiopathic weight reduction in mice deficient in the high mobility group transcription factor sox8
    Molecular and Cellular Biology, 2001
    Co-Authors: Elisabeth Sock, Katy Schmidt, Irm Hermannsborgmeyer, Michael R Bosl, Michael Wegner
    Abstract:

    The Sox protein family constitutes a group of transcription factors with an already large but still increasing number of family members. Its occurrence is confined to the animal kingdom, where Sox proteins have diverse functions both during Development and in the adult. These functions range from roles in early embryogenesis to functions in lineage specification and terminal differentiation events. Processes known to rely on Sox proteins include endoderm formation, neural induction, neural crest and lens Development, gliogenesis, chondrogenesis, hemopoiesis, and sex determination (for reviews, see references 5, 22, and 32). All family members are characterized by possession of a specific type of DNA-binding domain, the minor groove-interacting high-mobility-group domain. Sequence similarities outside this domain are found only between subsets of Sox proteins and provide criteria which further subdivide this protein family into subgroups A to G. These subgroups are present in organisms from Caenorhabditis elegans and Drosophila to humans (5, 32). Genes coding for Sox proteins of the same subgroup tend to have similar genomic organizations. One of the well-characterized groups of Sox proteins is subgroup E. It consists of the three members Sox8, Sox9, and Sox10, with Sox8 being the most recently identified (23, 25). Inactivation of a single Sox9 allele in humans is the cause of a severe skeletal malformation syndrome called campomelic dysplasia (7, 31). In male patients, campomelic dysplasia is often associated with XY sex reversal. In agreement with the observed phenotype, Sox9 expression is highest in chondrocytes and Sertoli cells of the testis (13, 17, 33). Other expression domains of Sox9 include brain, otic and nasal placode, lung, and kidney. These tissues are only rarely affected in campomelic dysplasia patients. The severity of the phenotype already observed in the heterozygous state might also explain why standard gene disruption techniques in mice have proven unsuccessful for Sox9. When homozygous Sox9-deficient ES cells were used to generate chimeras, Sox9-deficient ES cells failed to contribute to the chondrocyte population in these chimeric mice, impressively proving the essential role of Sox9 in this cell type (4). Many chondrocyte-specific genes are furthermore under direct control of Sox9, including the genes for type II collagen, type XI collagen, aggrecan, and cartilage-derived retinoic acid-sensitive protein genes (1, 15, 16, 26, 34). Sox10 on the other hand, is expressed first in the early neural crest, then throughout the forming peripheral nervous system (PNS), and finally in Glial cells of the PNS and central nervous system (CNS) (14). As in the case of Sox9, mutation or loss of a single Sox10 allele is already phenotypically apparent. Sox10 haploinsufficiency causes disturbances of neural crest Development that are visible as partial pigmentation defects and aganglionosis of the distal colon in mice and humans (6, 9, 24, 28). In humans, this defect is known as Waardenburg-Hirschsprung disease. Peripheral neuropathies are often associated with Sox10-dependent Waardenburg-Hirschsprung disease (27, 29), correlating with the strong expression of Sox10 at later times in peripheral glia (14). Central myelinopathies present a further, less frequent complication (11), in agreement with Sox10 expression in myelinating glia of the CNS (14). Inactivation or deletion of both Sox10 alleles in mice leads to a complete loss of neural crest-derived melanocytes and enteric nervous system and proves that Sox10 is an essential factor for all gliogenesis of the PNS (6, 21). Target genes of Sox10 include genes important for Glial Development (ErbB3 gene) and identity (protein zero gene) (6, 21). Recently, Sox8 was identified as the third group E Sox protein in mice, humans, and chickens (2, 23, 25). Existing reports on Sox8 expression are preliminary and partially contradictory, but they hint at expression during Development in many tissues and organs, including branchial arches, nervous system, eye, male gonad, kidney, and limbs. Prominent places of expression in the adult were brain and testis. Chromosomal localization of human SOX8 to 16p13.3 placed it in a region often deleted in patients with ATR-16 syndrome (characterized by a combination of α-thalassemia, facial malformations, and mental retardation) and targeted in a Japanese family by a translocation event causing microphthalmia and congenital cataract (microphthalmia-cataract syndrome [CATM]). Localization to the syntenic region on mouse chromosome 17 places Sox8 in proximity to the tw18 mutation which causes abnormal mesodermal cell migration and is lethal prior to organogenesis. In analogy to the case for Sox9 and Sox10, it appeared reasonable to assume that inactivation or deletion of Sox8 in mice should cause severe Developmental defects in some of the tissues that express it. The phenotype could then be instrumental in identifying Sox8-dependent disease phenotypes in humans. Here, we deleted the Sox8 gene by homologous recombination in ES cells and subsequently generated Sox8-deficient mice. The simultaneous replacement of the Sox8 gene by a lacZ marker allowed a detailed analysis of Sox8 expression and should have facilitated detection of Developmental defects in these mice. Surprisingly, homozygous Sox8-deficient mice failed to exhibit a major Developmental defect in any of the Sox8-specific expression domains. Despite a significant weight reduction, they were viable and fertile. Possible reasons for and implications of this unexpected finding are discussed.

  • the transcription factor sox10 is a key regulator of peripheral Glial Development
    Genes & Development, 2001
    Co-Authors: Stefan Britsch, Carmen Birchmeier, Dieter Riethmacher, Derk E Goerich, Reto I Peirano, Moritz J Rossner, Klausarmin Nave, Michael Wegner
    Abstract:

    The molecular mechanisms that determine Glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral Glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral Glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later Developmental stages, this lack of peripheral Glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in Development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10(Dom) mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10(Dom)/+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.

  • protein zero gene expression is regulated by the Glial transcription factor sox10
    Molecular and Cellular Biology, 2000
    Co-Authors: Reto I Peirano, Derk E Goerich, Dieter Riethmacher, Michael Wegner
    Abstract:

    The nervous system contains two major types of cells, neurons and glia. The task of Glial cells is to support Development, survival, and functionality of neurons. Glial cells are found associated with neuronal cell bodies as well as with axons. Vertebrates have developed special types of Glial cells that form multilamellar sheaths around axonal segments. These myelin sheaths act as electrical insulators and confine the spread of action potentials to the nodes of Ranvier which separate the myelinated segments. Myelinating glia are thus essential for the rapid saltatory conduction of nerve impulses that are characteristic of the vertebrate nervous system. The myelin sheath is a specialized organelle that contains a small number of highly abundant proteins (25). These include myelin basic protein, proteolipid protein (PLP), protein zero (P0), and peripheral myelin protein 22 (PMP-22). Whereas myelin basic protein is an integral part of myelin in both the central and peripheral nervous systems, other myelin proteins are essentially confined to either peripheral or central nervous system. PLP, for instance, is only expressed at low levels in Schwann cells, which constitute the myelinating cells of the peripheral nervous system. Furthermore, PLP is not integrated into Schwann cell myelin (16). In the central nervous system, however, PLP accounts for approximately 40% of total myelin protein, and PLP transcripts are highly abundant in oligodendrocytes, which are the myelinating cells of the central nervous system. For P0 and PMP-22, the situation is the exact reverse. Both are preferentially present in Schwann cells (24, 25). P0, in particular, seems to be expressed at significant levels in no cells other than those of the Schwann cell lineage. This transmembrane glycoprotein of the immunoglobulin superfamily is detected in neural crest cells committed to the Glial lineage and continues to be present throughout Development of the Schwann cell lineage at low levels (10, 21). Upon myelination, P0 expression is massively upregulated. As a consequence, P0 makes up more than 50% of the total myelin protein in mature Schwann cells, where it is directly involved in myelin compaction (1, 7, 26, 27, 42). Its highly restricted expression has made P0 an attractive target for the analysis of cell-specific transcriptional regulation. Using cultures of rat Schwann cells and transgenic mice, it was shown that a 1.1-kb promoter region of the rat P0 promoter is sufficient to mediate Schwann cell-specific expression both in vitro and in vivo (27, 29, 30). Transient transfections have been used to analyze this region in further detail. These experiments revealed the presence of a minimal promoter responsible for basal levels of transcription, as well as a strongly activating proximal and a modulatory distal region within this fragment (6). Although DNase footprinting experiments have succeeded in identifying a number of cis-acting sequences within the P0 promoter, the relevant trans-acting factors are not known. This situation is symptomatic for all myelin gene promoters studied to date. At the same time, a number of transcription factors which exhibit preferential expression in myelinating glia have been identified and found to be important for gliogenesis and maintenance of the Glial phenotype (for reviews, see references 31, 40, and 50). However, the target genes through which these factors act are not known. One of these transcription factors is Sox10 (19). This transcription factor belongs to the group of Sox proteins which contain as their DNA binding domain a high-mobility-group (HMG) box with similarity to the one originally identified in the mammalian sex-determining factor Sry (35, 47). During Development, Sox10 is first expressed widely in cells of the emerging neural crest (4, 19, 38, 46). Mutation of Sox10 therefore leads to a combination of neural crest defects that lead to embryonic lethality in homozygously affected mice and to pigmentation defects, deafness, and colonic aganglionosis in heterozygously affected mice and human patients suffering from combined Waardenburg-Hirschsprung syndrome (13, 36, 46). The neural crest-derived Schwann cell lineage also seemed to be affected in mice homozygous for the Sox10 mutation, arguing for a role of Sox10 in the early phases of Schwann cell Development (13). During late stages of embryogenesis and in the adult, Sox10 expression is primarily found in myelinating glia, including both Schwann cells and oligodendrocytes. This continued expression in myelinating glia clearly indicates that Sox10 has a function not only during early committment and determination but also during later stages of Glial Development. As for other Glial transcription factors, no target gene which could help to explain Sox10 function in Glial cells has so far been characterized. Here we show that the P0 gene is a direct transcriptional target of Sox10, thus providing both one of the first examples of a target gene for a Glial transcription factor and of a transcription factor intricately involved in the regulation of myelin-specific genes.

Christian Klambt - One of the best experts on this subject based on the ideXlab platform.

  • a transcriptional network controlling Glial Development in the drosophila visual system
    Development, 2015
    Co-Authors: Annchristin Bauke, Sofia Sasse, Till Matzat, Christian Klambt
    Abstract:

    In the nervous system, Glial cells need to be specified from a set of progenitor cells. In the developing Drosophila eye, perineurial glia proliferate and differentiate as wrapping glia in response to a neuronal signal conveyed by the FGF receptor pathway. To unravel the underlying transcriptional network we silenced all genes encoding predicted DNA-binding proteins in Glial cells using RNAi. Dref and other factors of the TATA box-binding protein-related factor 2 (TRF2) complex were previously predicted to be involved in cellular metabolism and cell growth. Silencing of these genes impaired early glia proliferation and subsequent differentiation. Dref controls proliferation via activation of the Pdm3 transcription factor, whereas Glial differentiation is regulated via Dref and the homeodomain protein Cut. Cut expression is controlled independently of Dref by FGF receptor activity. Loss- and gain-of-function studies show that Cut is required for Glial differentiation and is sufficient to instruct the formation of membrane protrusions, a hallmark of wrapping Glial morphology. Our work discloses a network of transcriptional regulators controlling the progression of a naive perineurial glia towards the fully differentiated wrapping glia.

  • the eye imaginal disc as a model to study the coordination of neuronal and Glial Development
    Fly, 2010
    Co-Authors: Marion Silies, Yeliz Yuvaaydemir, Sigridur Rut Franzdottir, Christian Klambt
    Abstract:

    A complex nervous system comprises two distinct cell types, neurons and Glial cells, whose Development, differentiation and function is mutually interdependent. Many studies contributed to uncovering the basic mechanisms determining neuronal and Glial fate and we are progressing enormously towards an understanding of how neurons interconnect to form intricate neuronal networks. However, the mechanisms used to couple neuronal and Glial Development remain largely obscure. Here we advocate the usefulness of the developing Drosophila compound eye as a new model to study the complex relationship between Glial and neuronal cells.

  • Glial Development in the drosophila cns requires concomitant activation of Glial and repression of neuronal differentiation genes
    Development, 1997
    Co-Authors: Kay Giesen, Thomas Hummel, Angelika Stollewerk, Stephen D Harrison, Andrew Travers, Christian Klambt
    Abstract:

    Two classes of Glial cells are found in the embryonic Drosophila CNS, midline Glial cells and lateral Glial cells. Midline Glial Development is triggered by EGF-receptor signalling, whereas lateral Glial Development is controlled by the gcm gene. Subsequent Glial cell differentiation depends partly on the pointed gene. Here we describe a novel component required for all CNS glia Development. The tramtrack gene encodes two zinc-finger proteins, one of which, ttkp69, is expressed in all non-neuronal CNS cells. We show that ttkp69 is downstream of gcm and can repress neuronal differentiation. Double mutant analysis and coexpression experiments indicate that Glial cell differentiation may depend on a dual process, requiring the activation of Glial differentiation by pointed and the concomitant repression of neuronal Development by tramtrack.

Heinrich Reichert - One of the best experts on this subject based on the ideXlab platform.

  • gliogenesis in drosophila genome wide analysis of downstream genes of Glial cells missing in the embryonic nervous system
    Development, 2002
    Co-Authors: Boris Egger, Ronny Leemans, Thomas Loop, Lars Kammermeier, Yun Fan, Tanja Radimerski, Martin Strahm, Ulrich Certa, Heinrich Reichert
    Abstract:

    In Drosophila, the Glial cells missing (gcm) gene encodes a transcription factor that controls the determination of Glial versus neuronal fate. In gcm mutants, presumptive Glial cells are transformed into neurons and, conversely, when gcm is ectopically misexpressed, presumptive neurons become glia. Although gcm is thought to initiate Glial cell Development through its action on downstream genes that execute the Glial differentiation program, little is known about the identity of these genes. To identify gcm downstream genes in a comprehensive manner, we used genome-wide oligonucleotide arrays to analyze differential gene expression in wild-type embryos versus embryos in which gcm is misexpressed throughout the neuroectoderm. Transcripts were analyzed at two defined temporal windows during embryogenesis. During the first period of initial gcm action on determination of Glial cell precursors, over 400 genes were differentially regulated. Among these are numerous genes that encode other transcription factors, which underscores the master regulatory role of gcm in gliogenesis. During a second later period, when Glial cells had already differentiated, over 1200 genes were differentially regulated. Most of these genes, including many genes for chromatin remodeling factors and cell cycle regulators, were not differentially expressed at the early stage, indicating that the genetic control of Glial fate determination is largely different from that involved in maintenance of differentiated cells. At both stages, Glial-specific genes were upregulated and neuron-specific genes were downregulated, supporting a model whereby gcm promotes Glial Development by activating Glial genes, while simultaneously repressing neuronal genes. In addition, at both stages, numerous genes that were not previously known to be involved in Glial Development were differentially regulated and, thus, identified as potential new downstream targets of gcm. For a subset of the differentially regulated genes, tissue-specific in vivo expression data were obtained that confirmed the transcript profiling results. This first genome-wide analysis of gene expression events downstream of a key Developmental transcription factor presents a novel level of insight into the repertoire of genes that initiate and maintain cell fate choices in CNS Development.

Emi Takahashi - One of the best experts on this subject based on the ideXlab platform.

  • high angular resolution diffusion mri reveals conserved and deviant programs in the paths that guide human cortical circuitry
    Cerebral Cortex, 2020
    Co-Authors: Christine J Charvet, Avilash Das, Jae W Song, Deselyn J Tindallburgess, Priya Kabaria, Guangping Dai, Tara Kane, Emi Takahashi
    Abstract:

    Diffusion magnetic resonance (MR) tractography represents a novel opportunity to investigate conserved and deviant Developmental programs between humans and other species such as mice. To that end, we acquired high angular resolution diffusion MR scans of mice [embryonic day (E) 10.5 to postnatal week 4] and human brains [gestational week (GW) 17-30] at successive stages of fetal Development to investigate potential evolutionary changes in radial organization and emerging pathways between humans and mice. We compare radial Glial Development as well as commissural Development (e.g., corpus callosum), primarily because our findings can be integrated with previous work. We also compare corpus callosal growth trajectories across primates (i.e., humans and rhesus macaques) and rodents (i.e., mice). One major finding is that the developing cortex of humans is predominated by pathways likely associated with a radial Glial organization at GW 17-20, which is not as evident in age-matched mice (E 16.5, 17.5). Another finding is that, early in Development, the corpus callosum follows a similar Developmental timetable in primates (i.e., macaques and humans) as in mice. However, the corpus callosum grows for an extended period of time in primates compared with rodents. Taken together, these findings highlight deviant Developmental programs underlying the emergence of cortical pathways in the human brain.

  • high angular resolution diffusion mri reveals conserved and deviant programs in the paths that guide human cortical circuitry
    bioRxiv, 2019
    Co-Authors: Christine J Charvet, Avilash Das, Jae W Song, Deselyn J Tindallburgess, Priya Kabaria, Guangping Dai, Tara Kane, Emi Takahashi
    Abstract:

    Abstract Diffusion MR tractography represents a novel opportunity to investigate conserved and deviant Developmental programs between humans and other species such as mice. To that end, we acquired high angular resolution diffusion MR scans of mice (embryonic day [E] 10.5 to post-natal week [PW] 4) and human brains (gestational week [GW] 17 to 30) at successive stages of fetal Development to investigate potential evolutionary changes in radial organization and emerging pathways between humans and mice. We compare radial Glial Development as well as commissural Development (e.g., corpus callosum), primarily because our findings can be integrated with previous work. We also compare corpus callosal growth trajectories across primates (i.e., humans, rhesus macaques) and rodents (i.e., mice). One major finding is that the developing cortex of humans is predominated by pathways likely associated with a radial Glial organization at GW 17-20, which is not as evident in age-matched mice (E 16.5, 17.5). Another finding is that, early in Development, the corpus callosum follows a similar Developmental timetable in primates (i.e., macaques, humans) as in mice. However, the corpus callosum grows for an extended period of time in primates compared with rodents. Taken together, these findings highlight deviant Developmental programs underlying the emergence of cortical pathways in the human brain.

Margot Mayerproschel - One of the best experts on this subject based on the ideXlab platform.

  • the tripotential Glial restricted precursor grp cell and Glial Development in the spinal cord generation of bipotential oligodendrocyte type 2 astrocyte progenitor cells and dorsal ventral differences in grp cell function
    The Journal of Neuroscience, 2002
    Co-Authors: Ninel Z. Gregori, Christoph Proschel, Mark Noble, Margot Mayerproschel
    Abstract:

    We have found that the tripotential Glial-restricted precursor (GRP) cell of the embryonic rat spinal cord can give rise in vitro to bipotential cells that express defining characteristics of oligodendrocyte-type-2 astrocyte progenitor cells (O2A/OPCs). Generation of O2A/OPCs is regulated by environmental signals and is promoted by platelet-derived growth factor (PDGF), thyroid hormone (TH) and astrocyte-conditioned medium. In contrast to multiple observations indicating that oligodendrocyte precursor cells in the embryonic day 14 (E14) spinal cord are ventrally restricted, GRP cells are already present in both the dorsal and ventral spinal cord at E13.5. Ventral-derived GRP cells, however, were more likely to generate O2A/OPCs and/or oligodendrocytes than were their dorsal counterparts when exposed to TH, PDGF, or even bone morphogenetic protein-4. The simplest explanation of our results is that oligodendrocyte generation occurs as a result of generation of GRP cells from totipotent neuroepithelial stem cells, of O2A/OPCs from GRP cells and, finally, of oligodendrocytes from O2A/OPCs. In this respect, the responsiveness of GRP cells to modulators of this process may represent a central control point in the initiation of this critical Developmental sequence. Our findings provide an integration between the earliest known Glial precursors and the well-studied O2A/OPCs while opening up new questions concerning the intricate spatial and temporal regulation of precursor cell differentiation in the CNS.