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College of Arts and Sciences
Biochemistry & Cell Biology
BCB HomeBCB PeopleFaculty ProfilesBernadette Holdener

Bernadette Holdener, Ph.D.

holdenerProfessor
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 lab is interested in understanding why normal development of the brain, lung, skeletal, and cardiovascular system require rare forms of oxygen-linked (O-) glycosylation. These unusual sugars modifications are critical for the function of a limited number of proteins with thrombospondin type I repeats (TSRs, O-linked glucose-fucose disaccharide) and epidermal growth factor motifs (EGFs, O-linked glucose). For our studies, we utilize mouse knockout or conditional knockout mutations to block the addition of these sugars to the protein modules. The mutant mice provide us with a better understanding of the molecular mechanisms that contribute to development of chondrodysplasias, hydrocephalus, bronchopulmonary dysplasia, and Marfan’s disease, and identify this subset of glycoproteins in modulating the composition of the extracellular matrix and bioavailability of key cell signaling molecules.

    Blocking addition of O-linked glucose-fucose to TSRs alters extracellular matrix composition and cell-signaling in developing bone and brain: Marked shortening of the bones occurs if the glucose-fucose disaccharide is not added to TSRs (Pofut2, Protein O-fucosyltransferase conditional mutant) or the fucose is not extended to the disaccharide (B3glct, Beta-3-glucosyltransferase mutant). In Pofut2 conditional mutants, chondrocyte development is delayed because of an altered fibrillin microfibril network with consequent changes in TGFb and BMP signaling. In B3glct mutants, preventing the elongation of fucose to the disaccharide also leads to congenital hydrocephalus resulting in part from altered polarity of the ependymal cells and likely aggregation of proteins in the central aqueduct. The primary effect of these mutations is likely on the ADAMTS/TSL family of secreted metalloproteinases and related proteins, and current studies focus on understanding whether loss of the O-linked disaccharide on ADAMTS/TSL family members alters their activity and/or extracellular matrix interactions.

    Blocking addition of O-linked glucose to EGFs alters fibrillin microfibril and elastic fibril networks in developing lung airway, alveoli, and blood vessels (unpublished): Protein O-glucosyltransferase 2 and 3 (POGLUT2 & 3) were recently shown to add O-linked glucose on EGFs of Fibrillin and Latent TGFb proteins. We are evaluating the effects of the Poglut2/3 double knockouts (DKOs) on cardiopulmonary development. The DKOs neonates are runted and die soon after birth from cardiopulmonary defects. Current studies focus on evaluating the impact of the Poglut2/3 DKO on the assembly and physical properties of the fibrillin microfibrils and the determining the consequence of these changes on cell-signaling and cell differentiation during airway branching and alveolarization and cardiovascular development.

  • Publications

    Neupane S, Williamson DB, Roth RA, Halabi CM, Haltiwanger RS, and Holdener BC (2024) Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues. Journal of Biological Chemistry DOI:https://doi.org/10.1016/j.jbc.2024.107445. (Editor’s Pick)

    Bernardinelli SJ, Sillato AR, Grady RC, Neupane S, Iti A, Haltiwanger RS, and Holdener BC (2023) O-fucosylation of thrombospondin type I repeats is dispensable for trafficking thrombospondin 1 to platelet secretory granules. Glycobiology 33:301-310.  https://doi.org10.1093/glycob/cwad006

    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