Positions
- Professor
-
Department of Molecular & Human Genetics
Baylor College of Medicine
- Professor
-
Genetics & Genomics Graduate Program
Baylor College of Medicine
- Professor
-
Program in Developmental Biology
Development, Disease Models & Therapeutics Graduate Program
Baylor College of Medicine
Education
- MD from Tehran University Of Medical Sciences
- 06/1994 - Tehran, Iran
- Post-Doctoral Fellowship at University Of Ottawa
- 03/2000 - Ottawa, Ontario Canada
- Post-Doctoral Fellowship at Baylor College Of Medicine
- 12/2006 - Houston, Texas United States
Honors & Awards
- Alagille Syndrome Accelerator Award, The Medical Foundation (2019)
- Glycobiology Significant Achievement Award, Society for Glycobiology and Oxford University Press (2017)
- Norton Rose Fulbright Faculty Excellence Award, BCM (2017)
- Alagille Syndrome Accelerator Award, The Medical Foundation (2015)
- Best Lecturer, 8-Stranded Beta-Barrel Jelly Roll Award, BCM (2014)
- John S. Dunn Research Scholar, UT-Houston (2011)
- Young Investigator Recognition Award, UT-Houston (2009)
- Basil O'Connor Award, March of Dimes (2008)
Professional Interests
- Biliary development and repair (Alagille syndrome)
- Glycosylation and deglycosylation in developmental signaling
- NGLY1 deficiency
Professional Statement
Glycosylation is the most common post-translational modification of extracellular and secreted proteins and plays major roles in various aspects of cellular and organismal biology. We use Drosophila and mouse genetics, cell culture experiments and biochemical assays (in collaboration) to understand the role of glycosylation in animal development and pathophysiology of human disease. A major focus of our work is on glycosyltransferases that add O-glucose glycans to epidermal growth factor-like (EGF) repeats and their role in the regulation of the Notch signaling pathway. Another project focuses on a cytoplasmic enzyme called N-glycanase 1, mutations that have been identified in a multi-system developmental disorder called NGLY1 deficiency. We hope that our findings will shed light on the pathophysiology of the human diseases caused or modified by alterations in the function of these enzymes and will provide a framework to identify mechanism-based therapies for them.Role of O-linked glycosylation in the regulation of Notch signaling. An evolutionarily conserved enzyme called POGLUT1 (Rumi) adds O-linked glucose to EGF repeats harboring a CXSX(P/A)C consensus motif. Several xylosyltransferases extend the O-glucose by adding one or two xylose residues to it. Notably, we have found that in some contexts, the Notch pathway is sensitive to the gene dosage of the enzymes responsible for the addition of the xylose-xylose-glucose-O glycans to EGF repeats. Moreover, our recent reports on the identification of hypomorphic POGLUT1 alleles in patients with a new form of limb-girdle muscular dystrophy (LGMD-2Z) indicate that myogenesis is highly sensitive to Notch glycosylation by POGLUT1. Our current studies are aimed at elucidating the molecular bases for tissue-specific regulation of Notch signaling by xylose-xylose-glucose-O glycans. Another major goal is to understand how the corresponding glycosyltransferases regulate Notch signaling in a dosage-dependent manner. These studies might help us establish a framework for therapeutic modulation of the Notch pathway in diseases caused or exacerbated by aberrant Notch signaling.
A mouse model for Alagille Syndrome. Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by a congenital cholangiopathy of variable severity accompanied by cardiac, skeletal, renal and other abnormalities. In 94% of cases, ALGS is caused by mutations in JAG1, which encodes one of the ligands for the Notch pathway. We have previously reported a mouse model for the ALGS and have identified Poglut1 as a dominant genetic suppressor of the ALGS biliary phenotypes. We have also identified the transcription factor Sox9 and another glycosyltransferase as novel dosage-sensitive modifiers of the Jag1[+/–] phenotypes in mice. Ongoing experiments are aimed at using this model and its genetic modifiers to better understand the pathophysiology of ALGS and to develop a therapy for this disease. This project has the potential to provide novel insight into the formation of the biliary tree, both during normal development and upon liver injury.
Using fly and mouse models to understand the pathophysiology of NGLY1 deficiency. Human patients with mutations in N-glycanase 1 exhibit a host of developmental abnormalities including a delay in physical and intellectual development, movement disorders, osteopenia and lack of tears. NGLY1 is a “deglycosylation” enzyme and is thought to remove N-linked glycans from misfolded proteins during ER-associated degradation (ERAD). Using flies, mice and mammalian cells, we have identified two major signaling pathways affected by the loss of NGLY1: BMP signaling and AMPK signaling. The goal of this project is to elucidate the mechanisms underlying the NGLY1 deficiency phenotypes and to identify potential therapeutic targets for this disease. This project is helping us redefine the roles of deglycosylation in ERAD.
Websites
Selected Publications
- Pandey A, Galeone A, Han SY, Story BA, Consonni G, Mueller WF, Steinmetz LM, Vaccari T and Jafar-Nejad H "Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila." Nature Communications. 2023;14:5667.
- Ortiz-Vitali JL, Wu J, Xu N, Shieh AW, Niknejad N, Takeuchi M, Paradas C, Lin C, Jafar-Nejad H, Haltiwanger RS, Wang SH and Darabi R "Disease modeling and gene correction of LGMDR21-iPSCs elucidates the role of POGLUT1 in skeletal muscle maintenance, regeneration and satellite cell niche." Molecular Therapy - Nucleic Acids. 2023;33:683-697. Pubmed PMID: 37650119
- Niknejad N, Fox D, Burwinkel JL, Zarrin-Khameh N, Cho S, Soriano A, Cast AE, Lopez MF, Huppert KA, Rigo F, Huppert SS, Jafar-Nejad P and Jafar-Nejad H "Antisense oligonucleotide silencing of a glycosyltransferase, Poglut1, improves the liver phenotypes in mouse models of Alagille syndrome." Hepatology. 2023;in press Pubmed PMID: 37021797
- Pandey A, Adams JM, Han SY, Jafar-Nejad H "NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology.." Cells. 2022;11:1155. Pubmed PMID: 35406718
- Pandey A*, Niknejad N*, Jafar-Nejad H "Multifaceted regulation of Notch signaling by glycosylation." Glycobiology. 2021 May 29;31:8-28. Pubmed PMID: 32472127
- Han SY, Pandey A, Moore T, Galeone A, Duraine L, Cowan TM, Jafar-Nejad H "A conserved role for AMP-activated protein kinase in NGLY1 deficiency." PLoS Genetics. 2020;16(12):e1009258.
- Galeone A, Adams JM, Matsuda S, Presa MF, Pandey A, Han SY, Tachida Y, Hirayama H, Vaccari T, Suzuki T, Lutz CM, Affolter M, Zuberi A, Jafar-Nejad H "Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation." eLife. 2020;9:e55596. Pubmed PMID: 32720893
- Servián-Morilla E, Cabrera-Serrano M, Johnson K, Pandey A, ..., Haltiwanger RS, Takeuchi H, Jafar-Nejad H, Straub V, Paradas C "POGLUT1 biallelic mutations cause a myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern." Acta Neuropathologica. 2020 Mar;139:565-582. Pubmed PMID: 31897643
- Adams JM, Huppert KA, Castro EC, Lopez MF, Niknejad N, Subramanian S, Zarrin-Khameh N, Finegold MJ, Huppert SS, Jafar-Nejad H "Sox9 is a modifier of the liver disease severity in a mouse model of Alagille syndrome." Hepatology. 2020 Apr;71:1331-1349. Pubmed PMID: 31469182
- Pandey A*, Harvey BM*, Lopez MF, Ito A, Haltiwanger RS, Jafar-Nejad H. "Glycosylation of specific Notch EGF repeats by Ofut1 and Fringe regulates Notch signaling in Drosophila." Cell Reports. 2019 Nov 12;29:2054-2066.e6. Pubmed PMID: 31722217
- Adams JM, Jafar-Nejad H "The roles of Notch signaling in liver development and disease." Biomolecules. 2019 Oct 14;9:608. Pubmed PMID: 31615106
- Niknejad N, Jafar-Nejad H "Unbiased glycomics: A powerful tool in rare disease diagnosis and research." Translational Research. 2019;206:1-4. Pubmed PMID: 30528322
- Adams JM, Jafar-Nejad H "Determining Bile Duct Density in the Mouse Liver." Journal of Visualized Experiments (JoVE). 2019 Apr 30;146:e59587. Pubmed PMID: 31107443
- Pandey A, Jafar-Nejad H "Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and Its Inhibition by Cis-Ligands." Journal of Visualized Experiments (JoVE). 2018;131:e56919. Pubmed PMID: 29364239
- Pandey A, Li-Kroeger D, Sethi MK, Lee TV, Buettner FFR, Bakker H, Jafar-Nejad H "Sensitized genetic backgrounds reveal differential roles for EGF repeat xylosyltransferases in Drosophila Notch signaling." Glycobiology. 2018;28:849-859. Pubmed PMID: 30169771
- Adams JM, Jafar-Nejad H "A new model of Alagille syndrome with broad phenotypic representation." Gastroenterology. 2018;154:803-806. Pubmed PMID: 29425927
- Lee TV*, Pandey A*, Jafar-Nejad H "Xylosylation of the Notch receptor preserves the balance between its activation by trans-Delta and inhibition by cis-ligands in Drosophila." PLoS Genetics. 2017;13:e1006723. Pubmed PMID: 28394891
- Galeone A, Han SY, Huang C, Hosomi A, Suzuki T, Jafar-Nejad H "Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1." eLife. 2017;6:e27612. Pubmed PMID: 28826503
- Wu J, Hunt SD, Matthias N, Servián-Morilla E, Lo J, Jafar-Nejad H, Paradas C, Darabi R "Generation of an induced pluripotent stem cell line (CSCRMi001-A) from a patient with a new type of limb-girdle muscular dystrophy (LGMD) due to a missense mutation in POGLUT1 (Rumi)." Stem Cell Research. 2017;24:102-105. Pubmed PMID: 29034878
- Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, Haltiwanger RS, Jafar-Nejad H "Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi)." Hepatology. 2016;doi: 10.1002/he. Pubmed PMID: 26235536
- Servián-Morilla E*, Takeuchi H*, Lee TV*, .. Haltiwanger RS, Jafar-Nejad H, and Paradas C "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss." EMBO Molecular Medicine. 2016;8:1289-1309. Pubmed PMID: 27807076
- Haltom AR, Jafar-Nejad H "The multiple roles of EGF repeat O-glycans in animal development.." Glycobiology. 2015 Oct;25:1027-42. Pubmed PMID: 26175457
- He P, Grotzke JE, NG B, Gunel M, Jafar-Nejad H, Cresswell P, Freeze HH "A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts.." Glycobiology. 2015 Aug;25:836-44. Pubmed PMID: 25900930
- Haltom AR*, Lee TV*, Harvey B, Leonardi J, Chen Y, Hong Y, Haltiwanger RS, Jafar-Nejad H "The protein O-glucosyltransferase Rumi modifies Eyes shut to promote rhabdomere separation in Drosophila." PLoS Genetics. 2014;10(11):e1004795. Pubmed PMID: 25412384
- LeBon L, Lee TV, Sprinzak D, Jafar-Nejad H, Elowitz M "Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states." eLife. 2014 Sep 25;3:e02950. Pubmed PMID: 25255098
- Leonardi J, Jafar-Nejad, H "Structure-function analysis of Drosophila Notch using genomic rescue transgenes.." Methods Mol Biol.. 2014;1187:29-46. Pubmed PMID: 25053479
- Lee TV, Jafar-Nejad H "O-Glucose glycans in Drosophila Notch signaling." Glycoscience: Biology and Medicine. 2014;849-856.
- Lee TV, Sethi MK, Leonardi J, Rana NA, Buettner FF, Haltiwanger RS, Bakker H, Jafar-Nejad H "Negative regulation of notch signaling by xylose.." PLoS Genetics. 2013 Jun;9(6):e1003547. Pubmed PMID: 23754965
- Takeuchi H, Fernández-Valdivia RC, Caswell DS, Nita-Lazar A, Rana NA, Garner TP, Weldeghiorghis TK, Macnaughtan MA, Jafar-Nejad H, Haltiwanger RS "Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase.." Proc. Natl. Acad. Sci. U.S.A.. 2011 Oct 4;108(40):16600-5. Pubmed PMID: 21949356
- Leonardi J*, Fernandez-Valdivia R*, Li YD, Simcox AA, Jafar-Nejad H "Multiple O-glucosylation sites on Notch function as a buffer against temperature-dependent loss of signaling.." Development. 2011 Aug;138(16):3569-78. Pubmed PMID: 21771811
- Fernandez-Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, Jafar-Nejad H "Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi.." Development. 2011 May;138(10):1925-34. Pubmed PMID: 21490058
- Lee TV, Takeuchi H, Jafar-Nejad H "Regulation of notch signaling via O-glucosylation insights from Drosophila studies.." Meth. Enzymol.. 2010;480:375-98. Pubmed PMID: 20816218
- Jafar-Nejad H, Leonardi J, Fernandez-Valdivia R "Role of glycans and glycosyltransferases in the regulation of Notch signaling.." Glycobiology. 2010 Aug;20(8):931-49. Pubmed PMID: 20368670
- Simcox AA, Austin CL, Jacobsen TL, Jafar-Nejad H "Drosophila embryonic 'fibroblasts': extending mutant analysis in vitro.." Fly (Austin). 2008;2(6):306-9. Pubmed PMID: 19077546
- Acar M*, Jafar-Nejad H*, Takeuchi H*, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ "Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling.." Cell. 2008 Jan 25;132(2):247-58. Pubmed PMID: 18243100
- Lim J, Jafar-Nejad H, Hsu YC, Choi KW "Novel function of the class I bHLH protein Daughterless in the negative regulation of proneural gene expression in the Drosophila eye.." EMBO Rep.. 2008 Nov;9(11):1128-33. Pubmed PMID: 18758436
- Rogaeva A, Ou XM, Jafar-Nejad H, Lemonde S, Albert PR "Differential repression by freud-1/CC2D1A at a polymorphic site in the dopamine-D2 receptor gene.." J. Biol. Chem.. 2007 Jul 20;282(29):20897-905. Pubmed PMID: 17535813
- Jafar-Nejad H, Tien AC, Acar M, Bellen HJ "Senseless and Daughterless confer neuronal identity to epithelial cells in the Drosophila wing margin.." Development. 2006 May;133(9):1683-92. Pubmed PMID: 16554363
- Acar M*, Jafar-Nejad H*, Giagtzoglou N, Yallampalli S, David G, He Y, Delidakis C, Bellen HJ "Senseless physically interacts with proneural proteins and functions as a transcriptional co-activator.." Development. 2006 May;133(10):1979-89. Pubmed PMID: 16624856
- Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, Jafar-Nejad H, Halder G "The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis.." Nat. Cell Biol.. 2006 Jan;8(1):27-36. Pubmed PMID: 16341207
- Jafar-Nejad H, Andrews HK, Acar M, Bayat V, Wirtz-Peitz F, Mehta SQ, Knoblich JA, Bellen HJ "Sec15, a component of the exocyst, promotes notch signaling during the asymmetric division of Drosophila sensory organ precursors.." Dev. Cell. 2005 Sep;9(3):351-63. Pubmed PMID: 16137928
- Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY "The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins.." Cell. 2005 Aug 26;122(4):633-44. Pubmed PMID: 16122429
- Jafar-Nejad H, Bellen HJ "Gfi/Pag-3/senseless zinc finger proteins: a unifying theme?." Mol. Cell. Biol.. 2004 Oct;24(20):8803-12. Pubmed PMID: 15456856
- Quan XJ, Denayer T, Yan J, Jafar-Nejad H, Philippi A, Lichtarge O, Vleminckx K, Hassan BA "Evolution of neural precursor selection: functional divergence of proneural proteins.." Development. 2004 Apr;131(8):1679-89. Pubmed PMID: 15084454
- Jafar-Nejad H, Acar M, Nolo R, Lacin H, Pan H, Parkhurst SM, Bellen HJ "Senseless acts as a binary switch during sensory organ precursor selection.." Genes Dev.. 2003 Dec 1;17(23):2966-78. Pubmed PMID: 14665671
- Ou XM, Lemonde S, Jafar-Nejad H, Bown CD, Goto A, Rogaeva A, Albert PR "Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene.." J. Neurosci.. 2003 Aug 13;23(19):7415-25. Pubmed PMID: 12917378
- Zhai RG, Hiesinger PR, Koh TW, Verstreken P, Schulze KL, Cao Y, Jafar-Nejad H, Norga KK, Pan H, Bayat V, Greenbaum MP, Bellen HJ "Mapping Drosophila mutations with molecularly defined P element insertions.." Proc. Natl. Acad. Sci. U.S.A.. 2003 Sep 16;100(19):10860-5. Pubmed PMID: 12960394
- Jafar-Nejad H, Norga K, Bellen H "Numb: Adapting" notch for endocytosis."." Dev. Cell. 2002 Aug;3(2):155-6. Pubmed PMID: 12194846
- Ou XM, Jafar-Nejad H, Storring JM, Meng JH, Lemonde S, Albert PR "Novel dual repressor elements for neuronal cell-specific transcription of the rat 5-HT1A receptor gene.." J. Biol. Chem.. 2000 Mar 17;275(11):8161-8. Pubmed PMID: 10713139
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