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Bernadette Holdener, Ph.D.

holdener Professor
Department of Biochemistry and Cell Biology

346 Centers for Molecular Medicine
Stony Brook University
Stony Brook, NY 11794-5215

Office telephone: 631-632-8292
Lab telephone: 631-632-8442  
Fax: 631-632-8575

E-mail:  bernadette.holdener@stonybrook.edu

  • Research Description

    My laboratory is interested in understanding why glycosylation of proteins is critical for embryo/fetal development. In particular, our studies focus on two unusual modifications found on proteins with thrombospondin type 1 (TSR) repeats ( O-linked glucose-fucose) or epidermal growth factor (EGF) modules ( O-linked glucose). Defects in TSR O-fucosylation or extension to the disaccharide block gastrulation and axis elongation in the early mouse embryo and interfere with development of the palate, craniofacial/skeletal system, and cause hydrocephalus. Blocking O-glucosylation of the EGF motifs leads to abnormalities in the skeletal system and lung alveoli and blood vessel development. To understand how loss of these sugars leads to these abnormalities, we utilize mouse knockout and conditional knockouts to eliminate the enzymes that add the sugars. Protein O-fucosyltransferase 2 (POFUT2) and beta -3-glucosyltransferase (B3GLCT) add the O-linked glucose fucose disaccharide to the properly folded TSR, and O-glucose is added to EGF modules by Protein O-glucosyltransferase 2 and 3 (POGLUT2 and POGLUT3). Our studies point to a role for these sugars in promoting efficient folding and trafficking of substrates as well as a role for the sugars on the secreted protein in modulating properties of the extracellular matrix including cell signaling and assembly.

  • Publications

    Neupane S, Berardinelli SJ, Cameron DC, Grady RC, Komatsu DE, Percival CJ, Takeuchi M, Ito A, Liu T-W, Nairn AV, Moremen K, Haltiwanger RS, Holdener BC (2022) O-fucosylation of thrombospondin type 1 repeats is essential for ECM remodeling and signaling during bone development.  Matrix Biology 107: 77-96. https://doi.org/10.1016/j.matbio.2022.02.002

    Neupane S, Goto J, Berardinelli SJ, Ito A, Haltiwanger RS, Holdener BC (2021) Hydrocephalus in mouse B3glct mutants is likely caused by defects in multiple B3GLCT substrates in ependymal cells and subcommissural organ. Glycobiology 9: 988-1004. https: doi: 10.1093/glycob/cwab033

    Zhang A, Berardinelli, SJ, Leonhard-Melief C, Vasudevan D, Liu, T-W, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS (2020) O-fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations. Journal of Biological Chemistry 295: 15742-15733. doi: https://doi.org/10.1074/jbc.RA120.014557

    Holdener BC, Percival CJ, Grady RC, Cameron DC, Berardinelli SJ, Zhang A, Neupane S, Takeuchi  M, Jimenez-Vega JC, Uddin SMZ, Komatsu DE, Honkanen R, Dubail J. Apte SS, Sato T, Narimatsu H, McClain SA, Haltiiwanger RS (2019) ADAMTS9 and ADAMTS20 are differentially affected by loss of B3glct in mouse model of Peters Plus Syndrom. Human Molecular Genetics 24:4053-4066 https://doi.org/10.1093/hmg/ddz225

    Holdener BC and Haltiwanger RS. (2019) Protein O-fucosylation: structure and function.  Current Opinion in Structural Biology 56: 78-86. doi: https://doi.org/10.1016/j.sbi.2018.12.005

    Siller SS, Sharma H, Li S, Yang J, Zhang Y, Holtzman MJ, Winuthayanon W, Colognato H, Holdener BC, Li FQ, Takemaru KI. (2017) Conditional knockout mice for the distal appendage protein CEP164 reveal its essential roles in airway multiciliated cell differentiation. PLoS Genet. 2017 Dec 15;13(12):e1007128. doi: 10.1371/journal.pgen.1007128. eCollection 2017 Dec. PMID: 29244804 Free PMC Article

    Benz BA, Nandadasa S, Takeuchi M, Grady RC, Takeuchi H, LoPilato RK, Kakuda S, Somerville RPT, Apte SS, Haltiwanger RS, and Holdener BC. (2016) Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion.  Dev Biol. doi:10.1016/j.ydbio.2016.05.038

    Taibi AV, Lighthouse JK, Grady RC, Shroyer KR, Holdener BC. (2013) Development of a conditional Mesd (mesoderm development) allele for functional analysis of the low-density lipoprotein receptor-related family in defined tissues. PloS one. 2013; 8(10):e75782. PMCID: PMC3790828

    Koehler, C, Lighthouse, J.K., Werther, T., Andersen, O.M., Diehl, A., Schnieder, D. Du, J., C Holdener, B.C., Oschkinat, H. (2011) The structure of MESD 45-184 brings light into the mechanism of LDLR family folding.  Cell Structure. 9: 337-348. PMID:21397185

    Lighthouse, J.K., Zhang, L., Hsieh, J-C., Rosenquist, T., and Holdener, B.C. (2011) MESD is Essential for Apical Localization of Megalin/LRP2 in the Visceral Endoderm. Developmental Dynamics. 240: 577-88. PMID: 21337463

    Du, J., Takeuchi, H., Leonhard-Melief, C., Shroyer,  K.R., Dlugosz, M., Haltiwanger, R.S., and Holdener, B.C. (2010) O-Fucosylation of Thrombospondin Type 1 Repeats Restricts Epithelial to Mesenchymal Transition (EMT) and Maintains Epiblast Pluripotency During Mouse Gastrulation.  Developmental Biology. 346:25-38. PMID: 20637190

    J-C. Hsieh, J-C., Lee, L., Zhang, L., Wefer, S., Brown, K., DeRossi, C., Wines, M.E., Rosenquist, T., and Holdener, B.C. (2003) Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity.  Cell. 112: 355-367. PMID: 12581525

    Laiosa, M.D., Lai, Z.W., Thurmond, T.S., Fiore, N.C., DeRossi, C., Holdener, B.C., Gasiewicz, T.A., Silverstone, A.E. (2002) 2,3,7,8-tetrachlorodibenzo-p-dioxin causes alterations in lymphocyte development and thymic atrophy in hemopoietic chimeras generated from mice deficient in ARNT2.  Toxicol. Sci. 69:117-124. PMID:12215665

    Wines, M.E., Lee, L., Katari, M.S., Zhang, L., DeRossi, C., Shi, Y., Perkins, S., Michael Feldman, M., McCombie, W.R., and Holdener, B.C. (2001) Identification of mesoderm development (mesd) candidate genes by comparative mapping and genome sequence analysis.  Genomics. 72: 88-98. PMID:10995574

    Michaud, J.L., DeRossi, C., May, N.R., Holdener, B.C., and Fan, C-M. (2000) ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mechanisms of Development 90: 253-261. PMID:10640708

    Wines, M., Shi, Y. Lindor, M., and Holdener, B.C. (2000) Physical localization of the mesoderm development (mesd) functional region in mouse.  Genomics. 68: 322-329. PMID:9722945

    Grimes, J.A., Nielsen, S.J., Battaglioli, E., Miska, E.A., Speh, J.C., Berry, D.L., Atouf, F., Holdener, B.C., Mandel, G., and Tony Kouzarides (2000) The Co-repressor mSin3A is a functional component of the RESTCoREST repressor complex.  J. Biol. Chem. 275: 9461-9467. PMID:10734093

    Holdener, B.C., Faust, C.J, Rosenthal, N., and Magnuson, T. msd is required for mesoderm induction in mice. (1994)  Development. 120: 1335-1346. PMID 8026341