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Scientist Emeritus

Heinz Arnheiter, M.D.

Basic Neuroscience Program


Building 35 Room 2A-201
35 Convent Drive MSC 3706
Bethesda MD 20892-3706
Office: (301) 496-1645
Lab: (301) 496-9661
Fax: (301) 480-2737

Dr. Arnheiter received his M.D. degree from the University of Zürich, Switzerland. His initial work at its Institute for Virology focused on the family of Mx proteins which are intrinsic host factors serving as the first lines of defense against infections with influenza viruses. He joined the former Laboratory of Molecular Genetics at NINDS to work on intracellular protein trafficking and viral assembly. After a brief time in Zürich, he returned to the NINDS and in 1986 introduced transgenic technology to the institute. He later shifted from studies of host defense mechanisms to the development of the nervous system, using the transgenic and knock-in technologies as a major research tools to elucidate molecular mechanisms of neural crest development and patterning of the neuroepithelium in the eye and neural tube. He retired from Government service at the end of 2011 and now serves as co-editor of the journal Pigment Cell and Melanoma Research.



Research Interests 1992-2011:

A detailed knowledge of the molecular mechanisms that govern the generation of distinct cell types from unspecified precursors will not only help us understand fundamental principles of normal ontogeny but also explain, and ultimately correct, instances where development has derailed and disease has resulted. It is in this context that in 1993, in collaboration with the Neal Copeland/Nancy Jenkins group at NCI, we isolated a novel basic-helix-loop-helix-zipper transcription factor gene that we called Mitf and whose mutations in mammals are associated with pigment cell disturbances, eye abnormalities, and hearing deficiencies (Waardenburg syndrome type II). My own group focused on cell lineage determination during the development of the eye where the bipotential optic neuroepithelium segregates into retina and retinal pigment epithelium, and of the neural crest where multipotential precursor cells give rise to MITF-positive melanoblasts and MITF-negative neuronal and glial cells of the peripheral nervous system. Work by many groups including ours revealed a considerable complexity by which MITF exerts its effects. In fact, the gene does not encode a single MITF protein but a family of distinct proteins generated by alternative promoter use, alternative splicing, and a host of post-translational modifications brought about by interactions with signaling pathways. Moreover, Mitf interacts with a number of other transcription factor genes in often surprising ways. For instance, both Mitf and Vsx2 mutations each severeley affect eye development, but their combination leads to a remarkable, though transient, improvement of eye development. In contrast, combinations of Mitf with Pax6 or Vax mutations lead to eye malformations that are more severe than those produced by either of the isolated mutations alone. These and other studies allowed us to determine molecular pathways that integrate many cell-intrinsic and cell-extrinsic factors that are crucial for the development and function of mammalian sensory organs.

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  • 1) Zaidi MR, Davis S, Noonan F, Graff-Cherry C, Hawley T, Walker RL, Feigenbaum L, Fuchs E, Lyak L, Young HA, Hornyak TJ, Arnheiter H, Trinchieri G, Meltzer PS, De Fabo EC, Merlino G. (2011)
  • Interferon-gamma links UV to melanocyte activation and promotes melanomagenesis.
  • Nature, 469, 548-553
  • 2) Bharti K, Gasper M, Bertuzzi S, Arnheiter H. (2011)
  • Lack of the ventral anterior homeodomain transcription factor VAX1 leads to induction of a secondary pituitary
  • Development, 138, 873-878
  • 3) Bharti K, Miller SS, Arnheiter H. (2011)
  • The new paradigm: Retinal pigment epithelium cells generated from embryonic stem cells or induced pluripotent cells
  • Pigment Cell Melanoma Research, 24, 21-34
  • 5) Wen B, Chen Y, Li H, Wang J, Shen J, Ma A, Qu J, Bismuth K, Debbache J, Arnheiter H, Hou L. (2010)
  • Allele-specific genetic interactions between Mitf and Kit affect melanocyte development
  • Pigment Cell and Melanoma Research, 23, 441-447
  • 6) Arnheiter, H. (2010)
  • The discovery of the microphthalmia locus and its gene, Mitf
  • Pigment Cell Melanoma Res, 23, 729-735
  • 7) Jia J, Arnheiter H and Li Z (2010)
  • Schizophrenia susceptibility gene DISC1 regulates dendritic spines through Kalirin-7 and Rac1
  • Cell Sci Reviews , 6(4), 13-19
  • 8) Skuntz, S, Mankoo, B, Nguyen, MTT, Hustert, E, Nakayama, A, Tournier-Lasserve, E, Wright, CVE, Pachnis, V, Bharti, K, Arnheiter, H. (2009)
  • Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton
  • Developmental Biology, 332, 383-395
  • 10) Bismuth, K., Skuntz, S., Hallsson, J.H., Pak, P., Dutra, A.B., Steingrimsson, E., Arnheiter, H. (2008)
  • An unstable targeted allele of the mouse Mitf gene with a high somatic and germ line reversion rate
  • Genetics, 178, 259-272
  • 11) Bharti, K, Liu, W, Csermely, T, Bertuzzi, S, Arnheiter, H. (2008)
  • Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF
  • Development, 135, 1169-1178
  • 12) Hallsson, JH, Haflidadottir, BS, Schepsky, A, Arnheiter, H, Steingrimsson, E (2007)
  • Evolutionary sequence comparison of the Mitf gene reveals novel conserved domains
  • Pigment Cell Research, 20, 185-200
  • 14) Bharti, K., Nguyen, M.-T. T., Skuntz, S., Nakayama, A., Bertuzzi, S., and Arnheiter, H. (2006)
  • The other pigment cell: Specification and development of the pigmented epithelium of the vertebrate eye
  • Pigment Cell Research, 19, 380-394
  • 15) Hou, L., Arnheiter, H. and Pavan, W.J. (2006)
  • Interspecies difference in the regulation of melanocyte development by SOX10 and MITF
  • Proc. Natl. Acad. Sci. (USA), 103, 9081-9085
  • 16) Horsford, D.J., Nguyen, M.T.T., Sellar, G., De Repentigny, Y., Kothary, R., Arnheiter, H., and McInnes, R.R. (2005)
  • Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity
  • Development, 132, 177-187
  • 17) Murakami, H. and Arnheiter, H. (2005)
  • Sumoylation modulates transcriptional activity of MITF in a promoter-specific manner
  • Pigment Cell Research, 18, 265-277
  • 18) Arnheiter H, Hou L, Nguyen MTT, Bismuth K, Csermely T, Murakami H, Skuntz S, Liu W, and Bharti K. (2005)
  • MITF - A Matter of Life and Death for the Developing Melanocytes.
  • From Melanocytes to Malignant Melanoma. Humana Press
  • 19) Bismuth, K., Maric, D., and Arnheiter, H. (2005)
  • MITF and cell proliferation: The role of alternative splice forms
  • Pigment Cell Research, 18, 349-359
  • 21) Hallsson JH, Haflidadottir BS, Stivers C, Odenwald W, Arnheiter H, Pignoni F, Steingrimsson E. (2004)
  • The basic helix-loop-helix leucine zipper transcription factor Mitf is conserved in Drosophila and functions in eye development
  • Genetics, 167(1), 233-41
  • 22) Kasai K, Takahashi M, Osumi N, Sinnarajah S, Takeo T, Ikeda H, Kehrl JH, Itoh G, Arnheiter H. (2004)
  • A role for the G12 family of heterotrimeric G proteins in Sonic hedgehog signaling
  • Genes Cells, 9, 49-58
  • 23) Hou L, Pavan WJ, Shin MK, Arnheiter H. (2004)
  • Cell-autonomous and cell non-autonomous signaling through Endothelin receptor B during melanocyte development
  • Development, 131, 3239-3247
  • 24) Alpan O, Bachelder E, Isil E., Arnheiter H, Matzinger P. (2004)
  • Educated dendritic cells act as messengers from memory to naive T helper cells
  • Nature Imm, 5, 615-622
  • 25) Hallsson JH, Haflidadottir BS, Stivers C, Odenwald W, Arnheiter H, Pignoni F, Steingrimsson E. (2004)
  • The bHLH-Zip transcription factor Mitf is conserved in Drosophila and functions in eye development
  • Genetics, 167, 233-241
  • 26) Mankoo BS, Skuntz S, Harrigan I, Grigorieva E, Candia A, Wright CVE, Arnheiter H, Pachnis V (2003)
  • Synergistic action of Meox homeobox genes upstream of genetic pathways essential for the patterning and differentiation of somites
  • Development, 130, 4655-4664
  • 27) Steingrimsson E, Arnheiter H, Hallsson JH, Lamoreux ML, Copeland G, Jenkins NA (2003)
  • Interallelic complementation at the mouse Mitf locus
  • Genetics, 163, 267-276
  • 28) Steingrimsson, E., Tessarollo, L., Pathak, B., Hou, L., Arnheiter, H. , Copeland, N.G. and Jenkins, N.A. (2002)
  • Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development
  • Proc. Natl. Acad. Sci. (USA), 99, 4477-4482
  • 29) Arnheiter H, Hou L, Nguyen MT, Nakayam A, Champagne B, Hallsson JH, Bismuth K (2002)
  • The role of Microphthalmia in pigment cell development
  • In: Mechanisms of Suntanning, Ortonne, J.-P. , Balotti, R. eds., Martin Dunitz Ltd, Publ. London., pp 49-63
  • 30) Potterf SB, Mollaaghababa R, Hou L, Southard-Smith EM, Hornyak TJ, Arnheiter H, Pavan WJ (2001)
  • Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase
  • Dev Biol, 237, 245-257
  • 31) Hou L., Panthier J.-J., Arnheiter, H. (2000)
  • Signaling and transcription regulation in the neural crest-derived melanocyte lineage: Interactions between KIT and MITF
  • Development, 127, 5379-5389
  • 32) Nguyen M-T T and Arnheiter H (2000)
  • Signaling and transcriptional regulation in early mammalian eye development: A link between FGF and MITF
  • Development, 127, 3581-3591
  • 33) Potterf SB, Furumura M, Dunn KJ, Arnheiter H, Pavan WJ (2000)
  • Transcription factor hierarchy in Waardenburg syndrome: Regulation of MITF expression by SOX10 and PAX3
  • Human Genet
  • 34) Hampton LL, Ladenheim EE, Akeson M, Way JM, Weber HC, Sutliff VE, Jensen RT, Wine LJ, Arnheiter H, Battey JF. (1998)
  • Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice.
  • Proc Natl Acad Sci USA, 95, 3188-3192
  • 35) Hodgkinson CA, Nakayama A, Li H, Swenson LB, Opdecamp K, Asher JH Jr, Arnheiter H, Glaser T. (1998)
  • Mutation at the anophthalmic white locus in Syrian hamsters: haploinsufficiency in the Mitf gene mimics
  • Hum Mol Genet, 7, 703-708
  • 36) Opdecamp K, Kos L, Arnheiter H, Pavan WJ. (1998)
  • Endothelin signalling in the development of neural crest-derived melanocytes
  • Biochem Cell Biol. , 76, 1093-1099
  • 37) Opdecamp K, Vanvooren P, Riviere M, Arnheiter H, Motta R, Szpirer J, Szpirer C. (1998)
  • The rat microphthalmia-associated transcription factor gene (Mitf) maps at 4q34-q41 and is mutated in the mib rats
  • Mamm Genome, 9, 617-621
  • 38) Arnheiter H. (1998)
  • Evolutionary biology. Eyes viewed from the skin
  • Nature, 391, 632-633
  • 39) Nakayama A et al. (1998)
  • Mutations in microphthalmia, the mouse homolog of the human deafness gene MITF, affect neuroepithelial and neural crest-derived melanocytes differently
  • Mech Dev, 70, 155-166
  • 40) Opdecamp K, Nakayama A, Nguyen MT, Hodgkinson CA, Pavan WJ, Arnheiter H. (1997)
  • Melanocyte development in vivo and in neural crest cell cultures: crucial dependence on the Mitf basic-helix-loop-helix-zipper transcription factor
  • Development, 124, 2377-2386
  • 41) Krylov D, Kasai K, Echlin DR, Taparowsky EJ, Arnheiter H, Vinson C. (1997)
  • A general method to design dominant negatives to B-HLHZip proteins that abolish DNA binding.
  • Proc Natl Acad Sci USA, 94, 12274-9
  • 42) Tachibana M, Perez-Jurado LA, Nakayama A, Hodgkinson CA, Li X, Schneider M, Miki T, Fex J, Francke U, Arnheiter H. (1994)
  • Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3.
  • Hum Mol Genet, 3, 553-557
  • 43) Steingrimsson E, Moore KJ, Lamoreux ML, Ferre-D'Amare AR, Burley SK, Zimring DC, Skow LC, Hodgkinson CA, Arnheiter H, Copeland NG, et al. (1994)
  • Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences.
  • Nat Genet, 8, 256-63
  • 44) Hemesath TJ, Steingrimsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, Arnheiter H, Copeland NG, Jenkins NA, Fisher DE. (1994)
  • microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family.
  • Genes Dev., 8, 2770-80
  • 45) Hodgkinson CA, Moore KJ, Nakayama A, Steingrimsson E, Copeland NG, Jenkins NA, Arnheiter H. (1993)
  • Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.
  • Cell, 74, 395-404
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