Christina Thaller

Baylor College of Medicine, Houston, Texas, United States

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Publications (65)548.66 Total impact

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    ABSTRACT: Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53-dependent c-Kit down-regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation.
    The Journal of Pathology 03/2011; 224(4):540-52. · 7.59 Impact Factor
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    ABSTRACT: Massive amounts of image data have been collected and continue to be generated for representing cellular gene expression throughout the mouse brain. Critical to exploiting this key effort of the post-genomic era is the ability to place these data into a common spatial reference that enables rapid interactive queries, analysis, data sharing, and visualization. In this paper, we present a set of automated protocols for generating and annotating gene expression patterns suitable for the establishment of a database. The steps include imaging tissue slices, detecting cellular gene expression levels, spatial registration with an atlas, and textual annotation. Using high-throughput in situ hybridization to generate serial sets of tissues displaying gene expression, this process was applied toward the establishment of a database representing over 200 genes in the postnatal day 7 mouse brain. These data using this protocol are now well-suited for interactive comparisons, analysis, queries, and visualization.
    Methods 02/2010; · 3.64 Impact Factor
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    ABSTRACT: Hindbrain networks important for sensation and arousal contain diverse neuronal populations with distinct projections, yet share specific characteristics such as neurotransmitter expression. The relationship between the function of these neurons, their developmental origin, and the timing of their migration remains unclear. Mice lacking the proneural transcription factor Math1 (Atoh1) lose neurons essential for hearing, balance, and unconscious proprioception. By using a new, inducible Math1(Cre*PR) allele, we found that Math1 is also required for the conscious proprioceptive system, including excitatory projection neurons of the dorsal column nuclei and for vital components of the interoceptive system, such as Barrington's nucleus, that is closely associated with arousal. In addition to specific networks, Math1 lineages shared specific neurotransmitter expression, including glutamate, acetylcholine, somatostatin, corticotropin releasing hormone, and nitric oxide. These findings identify twenty novel Math1 lineages and indicate that the Math1 network functions partly as an interface for conscious (early-born) and unconscious (late-born) proprioceptive inputs to the cortex and cerebellum, respectively. In addition, these data provide previously unsuspected genetic and developmental links between proprioception, interoception, hearing, and arousal.
    Proceedings of the National Academy of Sciences 12/2009; 106(52):22462-7. · 9.81 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.
    Proceedings of the National Academy of Sciences 12/2009; 106(51):21966-71. · 9.81 Impact Factor
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    ABSTRACT: A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
    Human Molecular Genetics 05/2009; 18(13):2431-42. · 7.69 Impact Factor
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    ABSTRACT: At spinal levels, sensory information pertaining to body positioning (proprioception) is relayed to the cerebellum by the spinocerebellar tracts (SCTs). In the past we revealed the basic helix-loop-helix transcription factor Atoh1 (Math1) to be important for establishing Dorsal Progenitor 1 (DP1) commissural interneurons, which comprise a subset of proprioceptive interneurons. Given there exists multiple subdivisions of the SCT we asked whether Atoh1 may also play a role in specifying other cell types in the spinal cord. Here, we reveal the generation of at least three DP1 derived interneuron populations that reside at spatially restricted positions along the rostral-caudal axis. Each of these cell populations expresses distinct markers and anatomically coincides with the cell bodies of the various subdivisions of the SCT. In addition, we found that as development proceeds (e.g. by E13.5) Atoh1 expression becomes apparent in the dorsal midline in the region of the roof plate (RP). Interestingly, we find that cells derived from Atoh1 expressing RP progenitors express SSEA-1, and in the absence of Atoh1 these progenitors become SOX9 positive. Altogether we reveal the existence of multiple Atoh1 dependent cell types in the spinal cord, and uncover a novel progenitor domain that arises late in development.
    Developmental Biology 01/2009; 327(2):339-51. · 3.87 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that ribbon synapses in the retina do not contain the t-SNARE (target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor) syntaxin 1A that is found in conventional synapses of the nervous system. In contrast, ribbon synapses of the retina contain the related isoform syntaxin 3. In addition to its localization in ribbon synapses, syntaxin 3 is also found in nonneuronal cells, where it has been implicated in the trafficking of transport vesicles to the apical plasma membrane of polarized cells. The syntaxin 3 gene codes for four different splice forms, syntaxins 3A, 3B, 3C, and 3D. We demonstrate here by using analysis of EST databases, RT-PCR, in situ hybridization, and Northern blot analysis that cells in the mouse retina express only syntaxin 3B. In contrast, nonneuronal tissues, such as kidney, express only syntaxin 3A. The two major syntaxin isoforms (3A and 3B) have an identical N-terminal domain but differ in the C-terminal half of the SNARE domain and the C-terminal transmembrane domain. These two domains are thought to be directly involved in synaptic vesicle fusion. The interaction of syntaxin 1A and syntaxin 3B with other synaptic proteins was examined. We found that both proteins bind Munc18/N-sec1 with similar affinity. In contrast, syntaxin 3B had a much lower binding affinity for the t-SNARE SNAP25 compared with syntaxin 1A. By using an in vitro fusion assay, we could demonstrate that vesicles containing syntaxin 3B and SNAP25 could fuse with vesicles containing synaptobrevin2/VAMP2, demonstrating that syntaxin 3B can function as a t-SNARE.
    The Journal of Comparative Neurology 11/2008; 510(5):550-9. · 3.66 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 1 is caused by expansion of a translated CAG repeat in ataxin1 (ATXN1). The level of the polyglutamine-expanded protein is one of the factors that contributes to disease severity. Here we found that miR-19, miR-101 and miR-130 co-regulate ataxin1 levels and that their inhibition enhanced the cytotoxicity of polyglutamine-expanded ATXN1 in human cells. We provide a new candidate mechanism for modulating the pathogenesis of neurodegenerative diseases sensitive to protein dosage.
    Nature Neuroscience 09/2008; 11(10):1137-9. · 15.25 Impact Factor
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    ABSTRACT: Patterning events during early eye formation determine retinal cell fate and can dictate the behavior of retinal ganglion cell (RGC) axons as they navigate toward central brain targets. The temporally and spatially regulated expression of bone morphogenetic proteins (BMPs) and their receptors in the retina are thought to play a key role in this process, initiating gene expression cascades that distinguish different regions of the retina, particularly along the dorsoventral axis. Here, we examine the role of BMP and a potential downstream effector, EphB, in retinotopic map formation in the lateral geniculate nucleus (LGN) and superior colliculus (SC). RGC axon behaviors during retinotopic map formation in wild-type mice are compared with those in several strains of mice with engineered defects of BMP and EphB signaling. Normal RGC axon sorting produces axon order in the optic tract that reflects the dorsoventral position of the parent RGCs in the eye. A dramatic consequence of disrupting BMP signaling is a missorting of RGC axons as they exit the optic chiasm. This sorting is not dependent on EphB. When BMP signaling in the developing eye is genetically modified, RGC order in the optic tract and targeting in the LGN and SC are correspondingly disrupted. These experiments show that BMP signaling regulates dorsoventral RGC cell fate, RGC axon behavior in the ascending optic tract, and retinotopic map formation in the LGN and SC through mechanisms that are in part distinct from EphB signaling in the LGN and SC.
    Journal of Neuroscience 08/2008; 28(28):7057-67. · 6.91 Impact Factor
  • Christina Thaller, Gregor Eichele
    Annals of the New York Academy of Sciences 06/2008; 785(1):1 - 11. · 4.38 Impact Factor
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    ABSTRACT: Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell-autonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.
    Proceedings of the National Academy of Sciences 02/2008; 105(4):1291-6. · 9.81 Impact Factor
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    ABSTRACT: Proneural factors represent <10 transcriptional regulators required for specifying all of the different neurons of the mammalian nervous system. The mechanisms by which such a small number of factors creates this diversity are still unknown. We propose that proteins interacting with proneural factors confer such specificity. To test this hypothesis we isolated proteins that interact with Math1, a proneural transcription factor essential for the establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures and identified the E-protein Tcf4. Interestingly, haploinsufficiency of TCF4 causes the Pitt-Hopkins mental retardation syndrome, underscoring the important role for this protein in neural development. To investigate the functional relevance of the Math1/Tcf4 interaction in vivo, we studied Tcf4(-/-) mice and found that they have disrupted pontine nucleus development. Surprisingly, this selective deficit occurs without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Importantly, deletion of any of the other E-protein-encoding genes does not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. Our findings provide the first in vivo evidence for an exclusive function of dimers formed between a proneural basic helix-loop-helix factor and a specific E-protein, offering insight about the mechanisms underlying transcriptional programs that regulate development of the mammalian nervous system.
    Proceedings of the National Academy of Sciences 09/2007; 104(39):15382-7. · 9.81 Impact Factor
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    ABSTRACT: Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and found heterozygous and mosaic mutations in PORCN in other affected females and males, respectively. PORCN encodes the human homolog of Drosophila melanogaster porcupine, an endoplasmic reticulum protein involved in secretion of Wnt proteins.
    Nature Genetics 08/2007; 39(7):836-8. · 35.21 Impact Factor
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    ABSTRACT: Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.
    Nature 02/2007; 445(7124):168-76. · 38.60 Impact Factor
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    ABSTRACT: Although glucocorticoids are known to elicit functional maturation of the gastrointestinal tract, the molecular mechanisms of glucocorticoid action on the developing intestine have not been fully elucidated. Our previous microarray studies identified 66 transcripts as being rapidly induced in the jejunum following dexamethasone (Dex) administration to suckling mice. Now we report the specific cellular location of a subset of these transcripts. Mouse pups at P8 received Dex or vehicle and intestinal segments were collected 3-4 h later. Robotic-based in situ hybridization (ISH) was performed with digoxygenin-labeled riboprobes. Transcripts studied included Ndrg1, Sgk1, Fos, and two unknown genes (Gene 9 and Gene 36). As predicted, ISH revealed marked diversity of cellular expression. In small intestinal segments, Sgk1 mRNA was in all epithelial cells; Fos mRNA was confined to epithelial cells at the villus tip; and Ndrg1 and Gene 36 mRNAs were localized to epithelial cells of the upper crypt and villus base. The remaining transcript (Gene 9) was induced modestly in villus stroma and strongly in the muscle layers. In the colon, Ndrg1, Sgk1, and Gene 36 were induced in all epithelial cells; Gene 9 was in muscle layers only; and Fos was not detectable. For jejunal segments, quantitation of ISH signals in tissue from Dex-treated and vehicle-treated mice demonstrated mRNA increases very similar to those measured by Northern blotting. We conclude that glucocorticoid action in the intestine reflects diverse molecular mechanisms operating in different cell types and that quantitative ISH is a valuable tool for studying hormone action in this tissue.
    AJP Gastrointestinal and Liver Physiology 01/2007; 291(6):G1041-50. · 3.65 Impact Factor
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    ABSTRACT: Rett syndrome (RTT), a postnatal neurodevelopmental disorder, is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Children with RTT display cognitive and motor abnormalities as well as autistic features. We studied mice bearing a truncated Mecp2 allele (Mecp2(308/Y) mice) and found evidence of increased anxiety-like behavior and an abnormal stress response as evidenced by elevated serum corticosterone levels. We found increased corticotropin-releasing hormone (Crh) gene expression in the paraventricular nucleus of the hypothalamus, the central amygdala, and the bed nucleus of the stria terminalis. Finally, we discovered that MeCP2 binds the Crh promoter, which is enriched for methylated CpG dinucleotides. In contrast, the MeCP2(308) protein was not detected at the Crh promoter. This study identifies Crh as a target of MeCP2 and implicates Crh overexpression in the development of specific features of the Mecp2(308/Y) mouse, thereby providing opportunities for clinical investigation and therapeutic intervention in RTT.
    Proceedings of the National Academy of Sciences 12/2006; 103(48):18267-72. · 9.81 Impact Factor
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    ABSTRACT: Sectioning tissues for optical microscopy often introduces upon the resulting sections distortions that make 3D reconstruction difficult. Here we present an automatic method for producing a smooth 3D volume from distorted 2D sections in the absence of any undistorted references. The method is based on pairwise elastic image warps between successive tissue sections, which can be computed by 2D image registration. Using a Gaussian filter, an average warp is computed for each section from the pairwise warps in a group of its neighboring sections. The average warps deform each section to match its neighboring sections, thus creating a smooth volume where corresponding features on successive sections lie close to each other. The proposed method can be used with any existing 2D image registration method for 3D reconstruction. In particular, we present a novel image warping algorithm based on dynamic programming that extends Dynamic Time Warping in 1D speech recognition to compute pairwise warps between high-resolution 2D images. The warping algorithm efficiently computes a restricted class of 2D local deformations that are characteristic between successive tissue sections. Finally, a validation framework is proposed and applied to evaluate the quality of reconstruction using both real sections and a synthetic volume.
    Journal of Neuroscience Methods 10/2006; 156(1-2):84-100. · 2.11 Impact Factor
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    ABSTRACT: Adenylate cyclases (Adcys) are components of several developmentally, neurophysiologically, and pharmacologically relevant signaling pathways. A prominent feature of Adcys is their ability to integrate multiple signaling pathways into a single second messenger pathway, the production of cAMP. Nine isoforms of membrane-bound Adcys are known, each encoded by a distinct gene. These isoforms differ in their response to regulatory upstream pathways as well as in their distribution in the brain and elsewhere. Use of various detection methods and animal species has, however, hampered a direct comparison of expression patterns, so the potential contribution of single isoforms to Adcy activity in different brain regions remains unclear. We have determined the expression patterns of all nine Adcy genes in the embryonic, postnatal day 7, and adult mouse brain by nonradioactive robotic in situ hybridization (ISH). Here we describe the salient features of these patterns. Regional colocalization of Adcy transcripts encoding isoforms with different regulatory properties was detected in the cortex, subregions of the hippocampus, olfactory bulb, thalamus, and striatum. Hence, our expression data support models for modulation of cAMP signaling by combinatorial action of multiple Adcy isoforms. However, in several instances, the expression domains of genes encoding isoforms with similar regulatory properties spatially exclude each other, which is most evident in not previously described expression domains of the embryonic midbrain roof. This is suggestive of functional specialization.
    The Journal of Comparative Neurology 07/2006; 496(5):684-97. · 3.66 Impact Factor
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    ABSTRACT: CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.
    The American Journal of Human Genetics 03/2006; 78(2):303-14. · 11.20 Impact Factor
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    ABSTRACT: A recently developed robotic platform termed "Genepaint" can carry out large-scale nonradioactive in situ hybridization (ISH) on tissue sections. We report a series of experiments that validate this novel platform. Signal-to-noise ratio and mRNA detection limits were comparable to traditional ISH procedures, and hybridization was transcript-specific, even in cases in which probes could have hybridized to several transcripts of a multigene family. We established an atlas of expression patterns of fibroblast growth factors (Fgfs) and their receptors (Fgfrs) for the embryonic day 14.5 mouse embryo. This atlas provides a comprehensive overview of previously known as well as novel sites of expression for this important family of signaling molecules. The Fgf/Fgfr atlas was integrated into the transcriptome database (www.genepaint.org), where individual Fgf and Fgfr expression patterns can be interactively viewed at cellular resolution and where sites of expressions can be retrieved using an anatomy-based search.
    Developmental Dynamics 11/2005; 234(2):371-86. · 2.59 Impact Factor

Publication Stats

6k Citations
548.66 Total Impact Points

Institutions

  • 1993–2011
    • Baylor College of Medicine
      • • Program in Cell and Molecular Biology
      • • Department of Neuroscience
      • • Department of Molecular & Human Genetics
      • • Program in Developmental Biology
      • • Department of Urology
      Houston, Texas, United States
  • 1990–2009
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2006
    • The American Society for Biochemistry and Molecular Biology
      McLean, Virginia, United States
    • Washington University in St. Louis
      • Department of Computer Science and Engineering
      Saint Louis, MO, United States
  • 2001–2006
    • Max Planck Institute for Experimental Medicine
      Göttingen, Lower Saxony, Germany
  • 1997
    • University of California, San Francisco
      • Department of Orthopaedic Surgery
      San Francisco, CA, United States
  • 1992
    • Vanderbilt University
      • Vanderbilt Center for Stem Cell Biology
      Nashville, MI, United States
  • 1991
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 1987–1990
    • Harvard University
      • Department of Molecular and Cell Biology
      Boston, MA, United States