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Sialoglycobiology in mammalian development

RESEARCH

 

Our group concentrates on the impact of sialic acids (Sia) during embryonic and early postnatal development. We use conditional knock-out and knock-down models targeting the sialic acid activating enzyme CMP-sialic acid synthetase (CMAS) in mice.

 

Every living cell is covered by a dense layer of glycoproteins, glycolipids and proteoglycans, the so called glycocalyx. Sialic acids are located at terminal positions on glycans and mediate cell-cell contacts and communications. The depletion of CMAS results in an asialo and embryonic lethal phenotype. Reduced CMAS expression causes kidney failure and postnatal death.

We aim to

  • Analyse the expression patterns of sialoglycans and elucidate their functions during development in mice
  • Provide mouse model systems to investigate the role of sialylation in fetal rejection, placentation deficits, preeclampsia, and nephropathies
  • Explain pathomechanisms associated with lack of Sia in mammals

 

Funding

 

2014-2017: DFG Normalverfahren (WE 5585/1-1). Title:“ Studien zur Bedeutung des negativ geladenen Zuckers Sialinsäure in der Embryonalentwicklung und für die Nierenfunktion.“

 

GROUP MEMBERS

PUBLICATIONS

 

Sieve I, Münster-Kühnel AK, Hilfiker-Kleiner D, (2017), Regulation and function of endothelial glycocalyx layer in vascular diseases, Vascul Pharmacol. 2017 Sep 12. pii: S1537-1891(17)30180-5. doi: 10.1016/j.vph.2017.09.002. [Epub ahead of print] Review.

 

Abeln M, Borst KM, Cajic S, Thiesler H, Kats E, Albers I, Kuhn M, Kaever V, Rapp E, Münster-Kühnel A, Weinhold B. Sialylation Is Dispensable for Early Murine Embryonic Development in Vitro. Chembiochem. 2017 Jul 4;18(13):1305-1316. doi:10.1002/cbic.201700083. Epub 2017 May 11.

Kröcher T, Röckle I, Diederichs U, Weinhold B, Burkhardt H, Yanagawa Y, Gerardy-Schahn R, Hildebrandt H. A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex. Development. 2014 Aug;141(15):3022-32. doi: 10.1242/dev.111773. Epub 2014 Jul 3

Tsuchiya A, Lu W-Y, Weinhold B, Boulter L, Stutchfield B, Williams M J, Guest R, Minnis-Lyons S, MacKinnon, A, Schwarzer D, Ichida T, Nomoto M, Aoyagi Y, Gerardy-Schahn R, Forbes S. PolySia-NCAM modulates the formation of ductular reactions in liver injury. Hepatology. 2014 Nov;60(5):1727-40. doi: 10.1002/hep.27099. Epub 2014 Sep 29.

Weinhold B, Gerardy-Schahn R, Münster-Kühnel A. Cytidine Monophosphate N-Acetylneuraminic Acid Synthetase (CMAS). Chapter 39 in Handbook of Glycosyltransferases and Related Genes, N. Taniguchi et al. (eds.), DOI: 10.1007/978-4-431-54240-7_39, pages 1545-1557, Springer Japan 2014.

Bartel J, Feuerstacke C, Galuska C, Weinhold B, Gerardy-Schahn R, Geyer R, Münster-Kühnel A, Middendorff R, and Galuska S. Laser microdissection of paraffin embedded tissue as a tool to estimate the sialylation status of selected cell populations. Analytical Chemistry 2014; 86, 2326-2331

Sellmeier M, Weinhold B, Münster-Kühnel A. CMP-Sialic acid Synthetase: The point of constriction in the sialylation pathway. Review. Topics in Current Chemistry 2015: 366-139, DOI: 10.1007/128_2013_477, Springer Berlin Heidelberg.

Kröcher T, Malinovskaja K, Jürgenson M, Aonurm-Helm A, Zharkovskaya T, Kalda A, Röckle I, Schiff M, Weinhold B, Gerardy-Schahn R, Hildebrandt H, Zharkovsky A. Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice. Brain Struct Funct. 2013 Sep 22: DOI 10.1007/s00429-013-0638-z

Weinhold B, Sellmeier M, Schaper W, Blume L, Philippens B, Kats E, Bernard U, Galuska SP, Geyer H, Geyer R, Worthmann K, Schiffer M, Groos S, Gerardy-Schahn R, Münster-Kühnel AK. Deficits in sialylation impair podocyte maturation. J Am Soc Nephrol. 2012 Aug;23 (8):1319-28. Epub 2012 Jun 28.

Schaper W, Bentrop J, Ustinova J, Blume L, Kats E, Tiralongo J, Weinhold B, Bastmeyer M, Muenster-Kuehnel A. Identification and biochemical characterization of two functional CMP-sialic acid synthetases in Danio rerio. J Biol Chem. 2012 Apr 13;287(16):13239-48. doi: 10.1074/jbc.M111.327544. Epub 2012 Feb 20.

Vogt J, Glumm R, Schlüter L, Schmitz D, Rost BR, Streu N, Rister B, Suman Bharathi B, Gagiannis D, Hildebrandt H,Weinhold B, Mühlenhoff M, Naumann T, Savaskan NE, Brauer AU, Reutter W, Heimrich B, Nitsch R, and Horstkorte R. (2012) Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting. Cell Mol Life Sci. 2011 Nov 9.  Epub.

Schiff M, Röckle I, Burkhardt H, Weinhold B, and Hildebrandt H. (2011) Thalamocortical pathfinding defects precede degeneration of the reticular thalamic nucleus in polysialic acid-deficient mice. J Neurosci.  31(4):1302-12.

Galuska SP, Rollenhagen M, Kaup M, Eggers K, Oltmann-Norden I, Schiff M, Hartmann M, Weinhold B, Hildebrandt H, Geyer R, Mühlenhoff M, and Geyer H. (2010) Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain. Proc Natl Acad Sci U S A. 107(22):10250-5.

Galuska SP, Geyer H, Weinhold B, Kontou M, Röhrich RC, Bernard U, Gerardy-Schahn R, Reutter W, Münster-Kühnel A, and Geyer R. (2010) Quantification of nucleotide-activated sialic acids by a combination of reduction and fluorescent labeling. Anal Chem. 82(11):4591-8.

Pekcec A, Weinhold B, Gerardy-Schahn R, and Potschka H. (2010) Polysialic acid affects pathophysiological consequences of status epilepticus. Neuroreport. 21(8):549-53.

Oschlies M, Dickmanns A, Haselhorst T, Schaper W, Stummeyer K, Tiralongo J, Weinhold B, Gerardy-Schahn R, von Itzstein M, Ficner R, and Münster-Kühnel AK. (2009) A C-terminal phosphatase module conserved in vertebrate CMP-sialic acid synthetases provides a tetramerization interface for the physiologically active enzyme. J Mol Biol. 393(1):83-97.

Schiff M, Weinhold B, Grothe C, and Hildebrandt H. (2009) NCAM and polysialyltransferase profiles match dopaminergic marker gene expression but polysialic acid is dispensable for development of the midbrain dopamine system. J Neurochem. 110(5):1661-73.

Drake PM, Stock CM, Nathan JK, Gip P, Golden KP, Weinhold B, Gerardy-Schahn R, and Bertozzi CR. (2009) Polysialic acid governs T-cell development by regulating progenitor access to the thymus. Proc Natl Acad Sci U S A. 106(29):11995-2000.

Hildebrandt H, Mühlenhoff M, Oltmann-Norden I, Röckle I, Burkhardt H, Weinhold B, and Gerardy-Schahn R. Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity. Brain. 132(Pt 10):2831-8.

Mühlenhoff M, Oltmann-Norden I, Weinhold B, Hildebrandt H, and Gerardy-Schahn R. (2009) Brain development needs sugar: the role of polysialic acid in controlling NCAM functions. Biol Chem. 390(7):567-74. Review.

Jungnickel J, Brämer C, Bronzlik P, Lipokatic-Takacs E, Weinhold B, Gerardy-Schahn R, and Grothe C. (2009) Level and localization of polysialic acid is critical for early peripheral nerve regeneration. Mol Cell Neurosci. 40(3):374-81.

Drake PM, Nathan JK, Stock CM, Chang PV, Muench MO, Nakata D, Reader JR, Gip P, Golden KP, Weinhold B, Gerardy-Schahn R, Troy FA 2nd, and Bertozzi CR. (2008) Polysialic acid, a glycan with highly restricted expression, is found on human and murine leukocytes and modulates immune responses. J Immunol. 181(10):6850-8.

Röckle I, Seidenfaden R, Weinhold B, Mühlenhoff M, Gerardy-Schahn R, and Hildebrandt H. (2008) Polysialic acid controls NCAM-induced differentiation of neuronal precursors into calretinin-positive olfactory bulb interneurons. Dev Neurobiol. 68(9):1170-84.

Potschka H, Pekcec A, Weinhold B, and Gerardy-Schahn R. (2008) Deficiency of neural cell adhesion molecule or its polysialylation modulates pharmacological effects of the AMPA receptor antagonist NBQX. Neuroscience. 152(4):1093-8.

Hildebrandt H, Mühlenhoff M, Weinhold B, and Gerardy-Schahn R. (2007) Dissecting polysialic acid and NCAM functions in brain development. J Neurochem. 103 Suppl 1:56-64. Review.

Senkov O, Sun M, Weinhold B, Gerardy-Schahn R, Schachner M, and Dityatev A. (2006) Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm. J Neurosci. 26(42):10888-109898.

Galuska SP, Oltmann-Norden I, Geyer H, Weinhold B, Kuchelmeister K, Hildebrandt H, Gerardy-Schahn R, Geyer R, and Mühlenhoff M. (2006) Polysialic acid profiles of mice expressing variant allelic combinations of the polysialyltransferases ST8SiaII and ST8SiaIV. J Biol Chem. 281(42):31605-15.

Stoenica L, Senkov O, Gerardy-Schahn R, Weinhold B, Schachner M, and Dityatev A. (2006) In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid. Eur J Neurosci. 23(9):2255-64.

Weinhold B, Seidenfaden R, Röckle I, Mühlenhoff M, Schertzinger F, Conzelmann S, Marth JD, Gerardy-Schahn R, and Hildebrandt H. (2005) Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule. J Biol Chem. 280(52):42971-7.

Münster-Kühnel AK, Tiralongo J, Krapp S, Weinhold B, Ritz-Sedlacek V, Jacob U, and Gerardy-Schahn R. (2004) Structure and function of vertebrate CMP-sialic acid synthetases. Glycobiology. 14(10):43R-51R. Review.

Münster AK, Weinhold B, Gotza B, Mühlenhoff M, Frosch M, and Gerardy-Schahn R. (2002) Nuclear localization signal of murine CMP-Neu5Ac synthetase includes residues required for both nuclear targeting and enzymatic activity. J Biol Chem. 277(22):19688-96.

Schratt G, Weinhold B, Lundberg AS, Schuck S, Berger J, Schwarz H, Weinberg RA, Rüther U, and Nordheim A. (2001) Serum response factor is required for immediate-early gene activation yet is dispensable for proliferation of embryonic stem cells. Mol Cell Biol. 21(8):2933-43.

Weinhold B, Schratt G, Arsenian S, Berger J, Kamino K, Schwarz H, Rüther U, and Nordheim A. (200) Srf(-/-) ES cells display non-cell-autonomous impairment in mesodermal differentiation. EMBO J. 19(21):5835-44.

Arsenian S, Weinhold B, Oelgeschläger M, Rüther U, and Nordheim A. (1998) Serum response factor is essential for mesoderm formation during mouse embryogenesis. EMBO J. 17(21):6289-99.

Weinhold B, and Rüther U. (1997) Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J. 327 (Pt 2):425-9.

Weinhold B, Bader A, Poli V, and Rüther U. (1997) Interleukin-6 is necessary, but not sufficient, for induction of the humanC-reactive protein gene in vivo. Biochem J. 1997 Aug 1;325 (Pt 3):617-21.

Eitner F, Westerhuis R, Burg M, Weinhold B, Gröne HJ, Ostendorf T, Rüther U, Koch KM, Rees AJ, and Floege J. (1997) Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo. Kidney Int. 51(1):69-78.