Irma Thesleff

University of Helsinki, Helsinki, Uusimaa, Finland

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Publications (289)1155.17 Total impact

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    ABSTRACT: Epithelial morphogenesis generates the shape of the tooth crown. This is driven by patterned differentiation of cells into enamel knots, root-forming cervical loops and enamel-forming ameloblasts. Enamel knots are signaling centers that define the positions of cusp tips in a tooth by instructing the adjacent epithelium to fold and proliferate. Here we show that the forkhead-box transcription factor Foxi3 inhibits formation of enamel knots and cervical loops and thus the differentiation of dental epithelium. Conditional deletion of Foxi3 (Foxi3 cKO) led to fusion of molars with abnormally patterned shallow cusps. Foxi3 was expressed in the epithelium, and its expression was reduced in the enamel knots and cervical loops as well as in ameloblasts. Bmp4, a known inducer of enamel knots and dental epithelial differentiation, downregulated Foxi3 in wild-type teeth. Using genome-wide gene expression profiling we showed that in Foxi3 cKO there was an early upregulation of differentiation markers, such as p21, Fgf15 and Sfrp5. Different signaling pathway components that are normally restricted to the enamel knots were expanded in the epithelium, and Sostdc1, a marker of the intercuspal epithelium was missing. These findings indicated that the activator-inhibitor balance regulating cusp patterning was disrupted in Foxi3 cKO. In addition, early molar bud morphogenesis and, in particular, formation of the suprabasal epithelial cell layer were impaired. We identified Keratin-10 as a marker of suprabasal epithelial cells in teeth. Our results suggest that Foxi3 maintains dental epithelial cells in an undifferentiated state and thereby regulates multiple stages of tooth morphogenesis.
    Development 10/2015; 142(22). DOI:10.1242/dev.124172 · 6.46 Impact Factor
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    ABSTRACT: Continuous growth of rodent incisors relies on epithelial stem cells (SCs) located in the SC niche called labial cervical loop (LaCL). Here we found a population of apoptotic cells residing in a specific location of the LaCL in mouse incisor. Activated Caspase3 and Caspase 9, expressed in this location colocalized in part with Lgr5 in putative stem cells. The addition of Caspase inhibitors to incisors ex vivo resulted in concentration dependent thickening of LaCL. To examine the role of Wnt signaling in regulation of apoptosis we exposed the LaCL of postnatal day 2 (P2) mouse incisor ex vivo to BIO, a known activator of Wnt/beta-catenin signaling. This resulted in marked thinning of LaCL as well as enhanced apoptosis. We found that Wnt/beta-catenin signaling was intensely induced by BIO in the mesenchyme surrounding the LaCL, but, unexpectedly, no beta-catenin activity was detected in the LaCL epithelium either before or after BIO treatment. We discovered that the expression of Fgf10, an essential growth factor for incisor epithelial SCs was dramatically down regulated in the mesenchyme around BIO-treated LaCL, and that exogenous Fgf10 could rescue the thinning of the LaCL caused by BIO. We conclude that the homeostasis of the epithelial SC population in the mouse incisor depends on a proper rate of apoptosis and that this apoptosis is controlled by signals from the mesenchyme surrounding the LaCL. Fgf10 is a key mesenchymal signal limiting apoptosis of incisor epithelial SCs and its expression is negatively regulated by Wnt/beta-catenin. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 02/2015; 33(5). DOI:10.1002/stem.1972 · 6.52 Impact Factor
  • Irma Thesleff ·
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    ABSTRACT: Tooth morphogenesis and cell differentiation are regulated by a chain of reciprocal interactions between the oral epithelium and underlying mesenchyme. Most genes that regulate tooth development seem to be associated with the four major signaling pathways: bone morphogenetic protein (BMP)/TGFβ, Wnt, Shh, and fibroblast growth factor (FGF). They are integrated at many levels and affect the functions of each other. Placodes and enamel knots are signaling centers in the dental epithelium and they regulate the initiation of teeth and the morphogenesis of the tooth crown, respectively. Ectodysplasin (Eda) (a tumor necrosis factor family signal) is a specific regulator of teeth and other organs developing as ectodermal appendages, and it affects the activity of the other major signal pathways. The disruption of the Eda pathway causes the syndrome hypohidrotic ectodermal dysplasia (HED). Modulating the various signal pathways in genetically modified mice generates differences in tooth number, shape and size. The initiation of teeth, as well as tooth replacement, appears to depend on the activity of Wnt signaling. Mutations in dozens of genes have been shown to cause aberrations in tooth development both in mice and humans. The most common dental defects in humans are hypodontia (missing teeth) and structural aberrations in dentin and enamel.
    Principles of Developmental Genetics, 01/2015: pages 393-405; , ISBN: 9780124059450
  • Irma Thesleff · Emma Juuri ·
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    ABSTRACT: The only dental epithelial cells present in adult human teeth are the cell rests of Malassez covering the roots as a thin network. They have been suggested to exhibit stem cell properties, but there is no evidence of their capacity to generate dental epithelium. So far, the continuously growing mouse incisor has provided the best model for research on dental epithelial stem cells. These cells reside in a niche located in the incisor cervical loop, and regulation of their maintenance, proliferation, and differentiation has been actively studied. All teeth originate from the embryonic primary dental lamina and replacement teeth develop from its extension, the successional dental lamina. Apparently, progenitors of all dental epithelial cell lineages reside in the dental lamina, and their differentiation is associated with tooth morphogenesis. Further characterization of the epithelial progenitor and stem cells and the determination of their capacity to generate whole teeth and/or enamel are goals worth pursuing in future research.
    Stem Cell Biology and Tissue Engineering in Dental Sciences, 01/2015: pages 263-270; , ISBN: 9780123971579
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    ABSTRACT: The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes.
    Journal of Dental Research 11/2014; 94(1). DOI:10.1177/0022034514556815 · 4.14 Impact Factor
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    ABSTRACT: Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium. It has been thought for decades that the dental mesenchymal stem cells giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue. Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.
    Nature 07/2014; DOI:10.1038/nature13536 · 41.46 Impact Factor
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    ABSTRACT: * = equally contributing authors Objectives: Embryonic glial cells along peripheral nerves can be viewed as a stem cell niche from which various cell types, including myelinating and non-myelinating Schwann cells, endoneural fibroblasts and melanocytes, arise during development. Peripheral nerves are intimately associated with the tooth anlagen during prenatal development, and we hypothesized that glial-derived cells could participate in tooth organogenesis. When fully developed, the tooth is densely innervated. With a potential role in tooth formation during development, we also aimed to investigate if nerve-associated Schwann cells could play important roles in the continuous growth and injury-induced repair of mouse incisors. Methods: We used mouse strains that allow for selective and permanent genetic labeling of peripheral glial cells. Immunohistochemistry and in situ hybridization were performed using standard protocols on 14 μm sagittal cryosections of embryonic heads, and 30 μm sections of the adult teeth. Both in vivo and in vitro techniques were used to study the effects of tooth damage, including FACS (Fluorescence-Activated Cell Sorting) analysis to validate data. Results: Our data show that progeny from peripheral nervous system glia give rise to dental mesenchymal stem cells and odontoblasts during development. Clonal fate mapping after single recombination events showed organized streams of pulp cells connected to domains of odontoblasts inserted into the odontoblast layer. Glia-derived dental mesenchymal stem cells stay in the self-renewing mouse incisor throughout the lifetime, and are involved in regeneration of the matrix after damage to the teeth. Conclusion: Our results demonstrate the existence of an unanticipated mechanism during craniofacial development. This mechanism involves conversion of nerve-associated glial cells into organ-forming mesenchymal stem cells during embryonic and adult tooth formation, as well as during regeneration after injury.
    IADR General Session and Exhibition 2014; 06/2014
  • Irma Thesleff ·

    Experimental Cell Research 04/2014; 325(2). DOI:10.1016/j.yexcr.2014.04.008 · 3.25 Impact Factor
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    ABSTRACT: Epithelial reorganization involves coordinated changes in cell shapes and movements. This restructuring occurs during formation of placodes, ectodermal thickenings that initiate the morphogenesis of epithelial organs including hair, mammary gland, and tooth. Signaling pathways in ectodermal placode formation are well known, but the cellular mechanisms have remained ill defined. We established imaging methodology for live visualization of embryonic skin explants during the first wave of hair placode formation. We found that the vast majority of placodal cells were nonproliferative throughout morphogenesis. We show that cell compaction and centripetal migration are the main cellular mechanisms associated with hair placode morphogenesis and that inhibition of actin remodeling suppresses placode formation. Stimulation of both ectodysplasin/NF-κB and Wnt/β-catenin signaling increased cell motility and the number of cells committed to placodal fate. Thus, cell fate choices and morphogenetic events are controlled by the same molecular pathways, providing the framework for coordination of these two processes.
    Developmental Cell 03/2014; 28(5):588-602. DOI:10.1016/j.devcel.2014.02.003 · 9.71 Impact Factor
  • Maria Jussila · Xenia Crespo Yanez · Irma Thesleff ·
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    ABSTRACT: Mammalian tooth development is characterized by formation of primary teeth that belong to different tooth classes and are later replaced by a single set of permanent teeth. The first primary teeth are initiated from the primary dental lamina, and the replacement teeth from the successional dental lamina at the lingual side of the primary teeth. An interdental lamina connects the primary tooth germs together. Most mammalian tooth development research is done on mouse, which does not have teeth in all tooth classes, does not replace its teeth, and does not develop an interdental lamina. We have used the ferret (Mustela putorius furo) as a model animal to elucidate the morphological changes and gene expression during the development of the interdental lamina and the initiation of primary teeth. In addition we have analyzed cell-cell signaling taking place in the interdental lamina as well as in the successional lamina during tooth replacement. By 3D reconstructions of serial histological sections we observed that the morphogenesis of the interdental lamina and the primary teeth are intimately linked. Expression of Pitx2 and Foxi3 in the interdental lamina indicates that it has odontogenic identity, and there is active signaling taking place in the interdental lamina. Bmp4 is coexpressed with the stem cell factor Sox2 at its lingual aspect suggesting that the interdental lamina may retain competence for tooth initiation. We show that when tooth replacement is initiated there is Wnt pathway activity in the budding successional lamina and adjacent mesenchyme but no active Fgf or Eda signaling. Genes associated with human tooth replacement phenotypes, including Runx2 and Il11rα, are mostly expressed in the mesenchyme around the successional lamina in the ferret. Our results highlight the importance of the dental lamina in the mammalian tooth development during the initiation of both primary and replacement teeth.
    Differentiation 01/2014; 87(1-2). DOI:10.1016/j.diff.2013.11.004 · 3.44 Impact Factor
  • Toshiyuki Yoshida · Yoshimi Takai · Irma Thesleff ·
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    ABSTRACT: Nectins constitute a family of four cell adhesion molecules which are localized on cell membrane. Mutations in NECTIN-1 gene cause the human ectodermal dysplasia syndrome (CLPED1) manifesting severe defects in skin and its appendages. However, nectin-1 null mutant mice have only a mild defect in epidermal stratification suggesting compensation by other nectins. We have analysed the epidermal and hair phenotypes of nectin-1; nectin-3 compound mutants. Epidermis was fragile and displayed severe defects in stratification, hair follicles were hypoplastic, and hair shaft structure was abnormal. Immunohistochemical analysis revealed severe defects in cell-cell junctions including adherens and tight junctions as well as desmosomes. It is therefore likely that the phenotypes were caused by impaired cell adhesion. The expression patterns of nectin-1 and nectin-3 together with the phenotypes in compound mutants indicated that heterophilic interactions between the two nectins are required for proper formation of epidermis and hair in mice. The nectin-1; nectin-3 compound mutant mice partially reproduced the phenotype of human CLPED1 patients.
    01/2014; 2014(6):1-12. DOI:10.1155/2014/432043
  • Irma Thesleff · Marja L. Mikkola ·

    Seminars in Cell and Developmental Biology 01/2014; 25-26. DOI:10.1016/j.semcdb.2014.02.002 · 6.27 Impact Factor
  • I Thesleff ·
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    ABSTRACT: Teeth are typical examples of organs in which genes determine the progress of development from initiation to the final shape, size and structure, whereas environmental factors play a minor role. Advances in gene technology over the last three decades have led to powerful novel methods to explore the mechanisms of embryonic development. Today we know a few hundred genes that regulate tooth development, and mutations in dozens of these genes have been shown to cause aberrations in tooth development in mice and/or humans. The functions of an increasing number of genes in tooth development have been discovered using genetically modified mouse models. We are now beginning to understand the 'programme' underlying the process of tooth formation. Key components of the programme are signals mediating communication between cells and complex gene regulatory networks in which the signal pathways are integrated. Understanding the mechanisms of tooth development at the level of genes, cells and molecules will lay the basis for new ways to prevent and treat dental defects and diseases. Over the last decade knowledge about dental stem cells has accumulated rapidly and novel stem cell technologies have been developed. Combining stem cell research with knowledge on the mechanisms of tooth development may open up novel possibilities for clinical tooth regeneration.
    Australian Dental Journal 11/2013; 59(s1). DOI:10.1111/adj.12102 · 1.10 Impact Factor
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    ABSTRACT: Ameloblastomas are locally invasive odontogenic tumors that exhibit a high rate of recurrence and often associate with the third molars. They are suggested to originate from dental epithelium because the tumor cells resemble epithelial cells of developing teeth. Expression of the transcription factor SOX2 has been previously localized in epithelial stem and progenitor cells in developing teeth as well as in various tumors. Here, we show that SOX2 is expressed in the epithelial cells of follicular and plexiform ameloblastomas. SOX2 was localized in the dental lamina of developing human primary molars. It was also expressed in the fragmented dental lamina associated with the third molars and in the epithelium budding from its posterior aspect in mice. However, no SOX2 expression was detected in either Hertwig's epithelial root sheath directing the formation of roots or in the epithelial cell rests of Malassez covering the completed roots. SOX2 was associated with supernumerary tooth formation in odontoma-like tumors induced by Wnt signal activation in mice. We propose that SOX2 functions in maintaining the progenitor state of epithelium in ameloblastomas and that ameloblastomas may originate from SOX2-expressing dental lamina epithelium.
    European Journal Of Oral Sciences 10/2013; 121(6). DOI:10.1111/eos.12095 · 1.49 Impact Factor
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    ABSTRACT: Background: Foxi3 is a member of the large forkhead box family of transcriptional regulators, which have a wide range of biological activities including manifold developmental processes. Heterozygous mutation in Foxi3 was identified in several hairless dog breeds characterized by sparse fur coat and missing teeth. A related phenotype called hypohidrotic ectodermal dysplasia (HED) is caused by mutations in the ectodysplasin (Eda) pathway genes. Results: Expression of Foxi3 was strictly confined to the epithelium in developing ectodermal appendages in mouse embryos, but no expression was detected in the epidermis. Foxi3 was expressed in teeth and hair follicles throughout embryogenesis, but in mammary glands only during the earliest stages of development. Foxi3 expression was decreased and increased in Eda loss- and gain-of-function embryos, respectively, and was highly induced by Eda protein in embryonic skin explants. Also activin A treatment up-regulated Foxi3 mRNA levels in vitro. Conclusions: Eda and activin A were identified as upstream regulators of Foxi3. Foxi3 is a likely transcriptional target of Eda in ectodermal appendage placodes suggesting that HED phenotype may in part be produced by compromised Foxi3 activity. In addition to hair and teeth, Foxi3 may have a role in nail, eye, and mammary, sweat, and salivary gland development.
    Developmental Dynamics 06/2013; 242(6). DOI:10.1002/dvdy.23952 · 2.38 Impact Factor
  • Irma Thesleff · Emma Juuri ·
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    ABSTRACT: This chapter contains sections titled: Developmental Anatomy Cellular and Molecular Mechanisms of Tooth Development Conclusions, Medical and Dental Implications, and Future Perspectives Summary References
    Mineralized Tissues in Oral and Craniofacial Science, 04/2013: pages 117-127; , ISBN: 9780470958339
  • Maria Jussila · Emma Juuri · Irma Thesleff ·
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    ABSTRACT: This chapter describes the developmental anatomy and molecular regulation of tooth initiation, morphogenesis, and cell differentiation, as well as of tooth renewal and replacement. Tooth morphogenesis is guided by interactions between epithelial and mesenchymal tissues and progresses through distinct stages defined by morphological features of the dental epithelium. Tooth morphogenesis is regulated by interactions between cells, in particular reciprocal and sequential interactions between the mesenchyme and epithelium. Tooth renewal and replacement require the action of stem cells that are capable of self-renewal and production of new progeny upon inductive signals. The study of tooth replacement using nonmodel animals for continuous lifelong tooth replacement, and the ferret for mammalian replacement, is generating new information on the mechanisms of successional tooth formation and the characteristics of dental stem and progenitor cells. For successful tooth regeneration, more detailed understanding is required of the gene regulatory networks and cellular mechanisms guiding tooth development.
    Stem Cells in Craniofacial Development and Regeneration, 03/2013: pages 109-134; , ISBN: 9781118279236
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    ABSTRACT: Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2+ cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2+ dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals.
    Development 03/2013; 140(7). DOI:10.1242/dev.089599 · 6.46 Impact Factor
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    ABSTRACT: Loss- and gain-of function approaches modulating canonical Wnt/β-catenin activity have established a role for the Wnt/β-catenin pathway during tooth development. Here we show that Wnt/β-catenin signaling is required in the dental mesenchyme for normal incisor development, as locally restricted genetic inactivation of β-catenin results in a splitting of the incisor placode, giving rise to two incisors. Molecularly this is first associated with down-regulation of Bmp4 and subsequent splitting of the Shh domain at a subsequent stage. The latter phenotype can be mimicked by ectopic application of the BMP antagonist Noggin. Conditional genetic inactivation of Bmp4 in the mesenchyme reveals that mesenchymal BMP4 activity is required for maintenance of Shh expression in the dental ectoderm. Taken together our results indicate that β-catenin together with Lef1 and Tcf1 are required to activate Bmp4 expression in order to maintain Shh expression in the dental ectoderm. This provides a mechanism whereby the number of incisors arising from one placode can be varied through local alterations of a mesenchymal signaling circuit involving β-catenin, Lef1, Tcf1 and Bmp4.
  • Jukka Jernvall · Irma Thesleff ·
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    ABSTRACT: Teeth are found in almost all vertebrates, and they therefore provide a general paradigm for the study of epithelial organ development and evolution. Here, we review the developmental mechanisms underlying changes in tooth complexity and tooth renewal during evolution, focusing on recent studies of fish, reptiles and mammals. Mammals differ from other living vertebrates in that they have the most complex teeth with restricted capacity for tooth renewal. As we discuss, however, limited tooth replacement in mammals has been compensated for in some taxa by the evolution of continuously growing teeth, the development of which appears to reuse the regulatory pathways of tooth replacement.
    Development 10/2012; 139(19):3487-97. DOI:10.1242/dev.085084 · 6.46 Impact Factor

Publication Stats

20k Citations
1,155.17 Total Impact Points


  • 1976-2015
    • University of Helsinki
      • • Institute of Biotechnology
      • • Institute of Dentistry
      • • Department of Pathology
      • • Department of Otolaryngology
      Helsinki, Uusimaa, Finland
  • 2005
    • Weizmann Institute of Science
      • Department of Molecular Genetics
      Rhovot, Central District, Israel
  • 1995
    • Academy of Sciences of the Czech Republic
      • Institute of Experimental Medicine
      Praha, Praha, Czech Republic
    • Karolinska Institutet
      • Department of Cell and Molecular Biology
      Сольна, Stockholm, Sweden
  • 1994
    • State University of New York
      New York, New York, United States
  • 1988
    • Friedrich Miescher Institute for Biomedical Research
      Bâle, Basel-City, Switzerland
  • 1980-1981
    • National Institutes of Health
      • Laboratory of Cell and Developmental Biology
      Maryland, United States