Daniela Berdnik

All Publications

• Plasma and CSF biomarkers of aging and cognitive decline in Caribbean vervets. Alzheimer's & dementia : the journal of the Alzheimer's Association Varma, C., Luo, E., Bostrom, G., Bathini, P., Berdnik, D., Wyss-Coray, T., Zhao, T., Dong, X., Ervin, F. R., Beierschmitt, A., Palmour, R. M., Lemere, C. A. 2024

  Abstract

  Vervets are non-human primates that share high genetic homology with humans and develop amyloid beta (Aβ) pathology with aging. We expand current knowledge by examining Aβ pathology, aging, cognition, and biomarker proteomics.Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies.We found age-related increases in Aβ deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aβ levels, revealing changes in proteins related to immune-related inflammation, metabolism, and cellular processes.Vervets are an effective model of aging and early-stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations.We found changes in immune and metabolic plasma biomarkers associated with age and cognition. Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes. TNFRSF19 (TROY) and Artemin co-localize with Alzheimer's disease pathology. Vervets are a relevant model for translational studies of early-stage Alzheimer's disease.

  View details for DOI 10.1002/alz.14038

  View details for PubMedID 38946666

• Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Nature Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. 2022

  Abstract

  The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

  View details for DOI 10.1038/s41586-022-04461-2

  View details for PubMedID 35236985

• Dysregulation of brain and choroid plexus cell types in severe COVID-19 (vol 595, pg 565, 2021) NATURE Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M., Channappa, D., Cobos, I., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., Wyss-Coray, T. 2021

  View details for DOI 10.1038/s41586-021-04080-3

  View details for Web of Science ID 000704968600001

  View details for PubMedID 34625744

  View details for PubMedCentralID PMC8500262

• Peripheral B-cells repress B-cell regeneration in aging through a TNFalpha/IGFBP-1/IGF1 immune-endocrine axis. Blood Dowery, R., Benhamou, D., Benchetrit, E., Harel, O., Nevelsky, A., Zisman-Rozen, S., Braun-Moscovici, Y., Balbir-Gurman, A., Avivi, I., Shechter, A., Berdnik, D., Wyss-Coray, T., Melamed, D. 2021

  Abstract

  Loss of B lymphocyte regeneration in the bone marrow (BM) is an immunological hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, thereby contributing to immune system dysfunction associated with aging. A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. In the present work, we uncover an immune-endocrine regulatory circuit that mediates cross-talk between peripheral B-cells and progenitors in the BM, to balance B-lymphopoiesis in both human and mouse aging. We found that tumor necrosis factor alpha (TNFalpha), which is highly produced by peripheral B-cells in aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds and sequesters insulin-like growth factor 1 (IGF1) in the circulation, thereby restraining its activity in promoting B-lymphopoiesis in the BM. Upon B-cell depletion in aged humans and mice, circulatory TNFalpha decreases, resulting in increased IGF1 and reactivation of B-lymphopoiesis. Perturbation of this circuit by administration of IGF1 to old mice or anti-TNFa antibodies to human patients restored B-lymphopoiesis in the BM. Hence, we suggest that in both human and mouse aging, peripheral B-cells utilize the TNFalpha/IGFBP-1/IGF1 axis to repress B-lymphopoiesis.

  View details for DOI 10.1182/blood.2021012428

  View details for PubMedID 34297797

• Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M. W., Channappa, D., Cobos, I., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., Wyss-Coray, T. 2021

  Abstract

  Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1-3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4-6. Synaptic signaling of upper-layer excitatory neurons-evolutionarily expanded in humans7 and linked to cognitive function8-are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.

  View details for DOI 10.1038/s41586-021-03710-0

  View details for PubMedID 34153974

• A neuronal blood marker is associated with mortality in old age. Nature aging Kaeser, S. A., Lehallier, B., Thinggaard, M., Häsler, L. M., Apel, A., Bergmann, C., Berdnik, D., Jeune, B., Christensen, K., Grönke, S., Partridge, L., Wyss-Coray, T., Mengel-From, J., Jucker, M. 2021; 1 (2): 218-225

  Abstract

  Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21-107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2-30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

  View details for DOI 10.1038/s43587-021-00028-4

  View details for PubMedID 37118632

  View details for PubMedCentralID 3756938

• Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stahli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., Vest, R. T., Chaney, A., Lehallier, B., Olsson, N., du Bois, H., Hsieh, R., Cropper, H. C., Berdnik, D., Li, L., Wang, E. Y., Traber, G. M., Bertozzi, C. R., Luo, J., Snyder, M. P., Elias, J. E., Quake, S. R., James, M. L., Wyss-Coray, T. 2020

  Abstract

  The vascular interfaceof the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as isstandard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

  View details for DOI 10.1038/s41586-020-2453-z

  View details for PubMedID 32612231

• A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 2020

  Abstract

  Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.

  View details for DOI 10.1038/s41586-020-2496-1

  View details for PubMedID 32669714

• Ageing hallmarks exhibit organ-specific temporal signatures. Nature Schaum, N. n., Lehallier, B. n., Hahn, O. n., Pálovics, R. n., Hosseinzadeh, S. n., Lee, S. E., Sit, R. n., Lee, D. P., Losada, P. M., Zardeneta, M. E., Fehlmann, T. n., Webber, J. T., McGeever, A. n., Calcuttawala, K. n., Zhang, H. n., Berdnik, D. n., Mathur, V. n., Tan, W. n., Zee, A. n., Tan, M. n., Pisco, A. O., Karkanias, J. n., Neff, N. F., Keller, A. n., Darmanis, S. n., Quake, S. R., Wyss-Coray, T. n. 2020

  Abstract

  Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

  View details for DOI 10.1038/s41586-020-2499-y

  View details for PubMedID 32669715

• Undulating changes in human plasma proteome profiles across the lifespan. Nature medicine Lehallier, B. n., Gate, D. n., Schaum, N. n., Nanasi, T. n., Lee, S. E., Yousef, H. n., Moran Losada, P. n., Berdnik, D. n., Keller, A. n., Verghese, J. n., Sathyan, S. n., Franceschi, C. n., Milman, S. n., Barzilai, N. n., Wyss-Coray, T. n. 2019; 25 (12): 1843–50

  Abstract

  Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.

  View details for DOI 10.1038/s41591-019-0673-2

  View details for PubMedID 31806903

• Multiple Click-Selective tRNA Synthetases Expand Mammalian Cell-Specific Proteomics JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yang, A. C., Du Bois, H., Olsson, N., Gate, D., Lehallier, B., Berdnik, D., Brewer, K. D., Bertozzi, C. R., Elias, J. E., Wyss-Coray, T. 2018; 140 (23): 7046–51

  Abstract

  Bioorthogonal tools enable cell-type-specific proteomics, a prerequisite to understanding biological processes in multicellular organisms. Here we report two engineered aminoacyl-tRNA synthetases for mammalian bioorthogonal labeling: a tyrosyl ( ScTyrY43G) and a phenylalanyl ( MmPheT413G) tRNA synthetase that incorporate azide-bearing noncanonical amino acids specifically into the nascent proteomes of host cells. Azide-labeled proteins are chemoselectively tagged via azide-alkyne cycloadditions with fluorophores for imaging or affinity resins for mass spectrometric characterization. Both mutant synthetases label human, hamster, and mouse cell line proteins and selectively activate their azido-bearing amino acids over 10-fold above the canonical. ScTyrY43G and MmPheT413G label overlapping but distinct proteomes in human cell lines, with broader proteome coverage upon their coexpression. In mice, ScTyrY43G and MmPheT413G label the melanoma tumor proteome and plasma secretome. This work furnishes new tools for mammalian residue-specific bioorthogonal chemistry, and enables more robust and comprehensive cell-type-specific proteomics in live mammals.

  View details for DOI 10.1021/jacs.8b03074

  View details for Web of Science ID 000435525500001

  View details for PubMedID 29775058

• Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018; 562 (7727): 367–72

  Abstract

  Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

  View details for DOI 10.1038/s41586-018-0590-4

  View details for PubMedID 30283141

• Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control JOURNAL OF VIROLOGY Ruiz-Riol, M., Berdnik, D., Llano, A., Mothe, B., Galvez, C., Perez-Alvarez, S., Oriol-Tordera, B., Olvera, A., Silva-Arrieta, S., Meulbroek, M., Pujol, F., Coll, J., Martinez-Picado, J., Ganoza, C., Sanchez, J., Gomez, G., Wyss-Coray, T., Brander, C. 2017; 91 (16)

  Abstract

  Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/β-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach ("communicome") has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda.

  View details for PubMedID 28592538

  View details for PubMedCentralID PMC5533920

• Human umbilical cord plasma proteins revitalize hippocampal function in aged mice NATURE Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., Hinkson, I. V., Angst, M. S., Wyss-Coray, T. 2017; 544 (7651): 488-?

  Abstract

  Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

  View details for DOI 10.1038/nature22067

  View details for PubMedID 28424512

• Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B., Simmons, D. A., Xie, X. S., Longo, F. M., Wyss-Coray, T. 2014; 20 (6): 659-663

  Abstract

  As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

  View details for DOI 10.1038/nm.3569

  View details for PubMedID 24793238

  View details for PubMedCentralID PMC4224436

• APOE {varepsilon}4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology Kerchner, G. A., Berdnik, D., Shen, J. C., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Wyss-Coray, T., Rutt, B. K. 2014; 82 (8): 691-697

  Abstract

  Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

  View details for DOI 10.1212/WNL.0000000000000154

  View details for PubMedID 24453080

• The sox gene Dichaete is expressed in local interneurons and functions in development of the Drosophila adult olfactory circuit DEVELOPMENTAL NEUROBIOLOGY Melnattur, K. V., Berdnik, D., Rusan, Z., Ferreira, C. J., Nambu, J. R. 2013; 73 (2): 107-126

  Abstract

  In insects, the primary sites of integration for olfactory sensory input are the glomeruli in the antennal lobes. Here, axons of olfactory receptor neurons synapse with dendrites of the projection neurons that relay olfactory input to higher brain centers, such as the mushroom bodies and lateral horn. Interactions between olfactory receptor neurons and projection neurons are modulated by excitatory and inhibitory input from a group of local interneurons. While significant insight has been gleaned into the differentiation of olfactory receptor and projection neurons, much less is known about the development and function of the local interneurons. We have found that Dichaete, a conserved Sox HMG box gene, is strongly expressed in a cluster of LAAL cells located adjacent to each antennal lobe in the adult brain. Within these clusters, Dichaete protein expression is detected in both cholinergic and GABAergic local interneurons. In contrast, Dichaete expression is not detected in mature or developing projection neurons, or developing olfactory receptor neurons. Analysis of novel viable Dichaete mutant alleles revealed misrouting of specific projection neuron dendrites and axons, and alterations in glomeruli organization. These results suggest noncell autonomous functions of Dichaete in projection neuron differentiation as well as a potential role for Dichaete-expressing local interneurons in development of the adult olfactory circuitry.

  View details for DOI 10.1002/dneu.22038

  View details for Web of Science ID 000313546400001

  View details for PubMedID 22648855

  View details for PubMedCentralID PMC3517933

• The SUMO Protease Verloren Regulates Dendrite and Axon Targeting in Olfactory Projection Neurons JOURNAL OF NEUROSCIENCE Berdnik, D., Favaloro, V., Luo, L. 2012; 32 (24): 8331-8340

  Abstract

  Sumoylation is a post-translational modification regulating numerous biological processes. Small ubiquitin-like modifier (SUMO) proteases are required for the maturation and deconjugation of SUMO proteins, thereby either promoting or reverting sumoylation to modify protein function. Here, we show a novel role for a predicted SUMO protease, Verloren (Velo), during projection neuron (PN) target selection in the Drosophila olfactory system. PNs target their dendrites to specific glomeruli within the antennal lobe (AL) and their axons stereotypically into higher brain centers. We uncovered mutations in velo that disrupt PN targeting specificity. PN dendrites that normally target to a particular dorsolateral glomerulus instead mistarget to incorrect glomeruli within the AL or to brain regions outside the AL. velo mutant axons also display defects in arborization. These phenotypes are rescued by postmitotic expression of Velo in PNs but not by a catalytic domain mutant of Velo. Two other SUMO proteases, DmUlp1 and CG12717, can partially compensate for the function of Velo in PN dendrite targeting. Additionally, mutations in SUMO and lesswright (which encodes a SUMO conjugating enzyme) similarly disrupt PN targeting, confirming that sumoylation is required for neuronal target selection. Finally, genetic interaction studies suggest that Velo acts in SUMO deconjugation rather than in maturation. Our study provides the first in vivo evidence for a specific role of a SUMO protease during neuronal target selection that can be dissociated from its functions in neuronal proliferation and survival.

  View details for DOI 10.1523/JNEUROSCI.6574-10.2012

  View details for Web of Science ID 000305295600024

  View details for PubMedID 22699913

  View details for PubMedCentralID PMC3394434

• MicroRNA Processing Pathway Regulates Olfactory Neuron Morphogenesis CURRENT BIOLOGY Berdnik, D., Fan, A. P., Potter, C. J., Luo, L. 2008; 18 (22): 1754-1759

  Abstract

  The microRNA (miRNA) processing pathway produces miRNAs as posttranscriptional regulators of gene expression. The nuclear RNase III Drosha catalyzes the first processing step together with the dsRNA binding protein DGCR8/Pasha generating pre-miRNAs [1, 2]. The next cleavage employs the cytoplasmic RNase III Dicer producing miRNA duplexes [3, 4]. Finally, Argonautes are recruited with miRNAs into an RNA-induced silencing complex for mRNA recognition (Figure 1A). Here, we identify two members of the miRNA pathway, Pasha and Dicer-1, in a forward genetic screen for mutations that disrupt wiring specificity of Drosophila olfactory projection neurons (PNs). The olfactory system is built as discrete map of highly stereotyped neuronal connections [5, 6]. Each PN targets dendrites to a specific glomerulus in the antennal lobe and projects axons stereotypically into higher brain centers [7-9]. In selected PN classes, pasha and Dicer-1 mutants cause specific PN dendrite mistargeting in the antennal lobe and altered axonal terminations in higher brain centers. Furthermore, Pasha and Dicer-1 act cell autonomously in postmitotic neurons to regulate dendrite and axon targeting during development. However, Argonaute-1 and Argonaute-2 are dispensable for PN morphogenesis. Our findings suggest a role for the miRNA processing pathway in establishing wiring specificity in the nervous system.

  View details for DOI 10.1016/j.cub.2008.09.045

  View details for Web of Science ID 000261244800025

  View details for PubMedID 19013069

  View details for PubMedCentralID PMC2612040

• piggyBac-based mosaic screen identifies a postmitotic function for cohesin in regulating developmental axon pruning DEVELOPMENTAL CELL Schuldiner, O., Berdnik, D., Levy, J. M., Wu, J. S., Luginbuhl, D., Camille Gontang, A., Luo, L. 2008; 14 (2): 227-238

  Abstract

  Developmental axon pruning is widely used to refine neural circuits. We performed a mosaic screen to identify mutations affecting axon pruning of Drosophila mushroom body gamma neurons. We constructed a modified piggyBac vector with improved mutagenicity and generated insertions in >2000 genes. We identified two cohesin subunits (SMC1 and SA) as being essential for axon pruning. The cohesin complex maintains sister-chromatid cohesion during cell division in eukaryotes. However, we show that the pruning phenotype in SMC1(-/-) clones is rescued by expressing SMC1 in neurons, revealing a postmitotic function. SMC1(-/-) clones exhibit reduced levels of the ecdysone receptor EcR-B1, a key regulator of axon pruning. The pruning phenotype is significantly suppressed by overexpressing EcR-B1 and is enhanced by a reduced dose of EcR, supporting a causal relationship. We also demonstrate a postmitotic role for SMC1 in dendrite targeting of olfactory projection neurons. We suggest that cohesin regulates diverse aspects of neuronal morphogenesis.

  View details for DOI 10.1016/j.devce1.2007.11.001

  View details for Web of Science ID 000253241400012

  View details for PubMedID 18267091

  View details for PubMedCentralID PMC2268086

• Temporal target restriction of olfactory receptor neurons by Semaphorin-1a/PlexinA-mediated axon-axon interactions NEURON Sweeney, L. B., Couto, A., Chou, Y., Berdnik, D., Dickson, B. J., Luo, L., Komiyama, T. 2007; 53 (2): 185-200

  Abstract

  Axon-axon interactions have been implicated in neural circuit assembly, but the underlying mechanisms are poorly understood. Here, we show that in the Drosophila antennal lobe, early-arriving axons of olfactory receptor neurons (ORNs) from the antenna are required for the proper targeting of late-arriving ORN axons from the maxillary palp (MP). Semaphorin-1a is required for targeting of all MP but only half of the antennal ORN classes examined. Sema-1a acts nonautonomously to control ORN axon-axon interactions, in contrast to its cell-autonomous function in olfactory projection neurons. Phenotypic and genetic interaction analyses implicate PlexinA as the Sema-1a receptor in ORN targeting. Sema-1a on antennal ORN axons is required for correct targeting of MP axons within the antennal lobe, while interactions amongst MP axons facilitate their entry into the antennal lobe. We propose that Sema-1a/PlexinA-mediated repulsion provides a mechanism by which early-arriving ORN axons constrain the target choices of late-arriving axons.

  View details for DOI 10.1016/j.neuron.2006.12.022

  View details for Web of Science ID 000245126600006

  View details for PubMedID 17224402

• Mitotic activation of the kinase Aurora-A requires its binding partner Bora. Developmental cell Hutterer, A., Berdnik, D., Wirtz-Peitz, F., Zigman, M., Schleiffer, A., Knoblich, J. A. 2006; 11 (2): 147-57

  Abstract

  The protein kinase Aurora-A is required for centrosome maturation, spindle assembly, and asymmetric protein localization during mitosis. Here, we describe the identification of Bora, a conserved protein that is required for the activation of Aurora-A at the onset of mitosis. In the Drosophila peripheral nervous system, bora mutants have defects during asymmetric cell division identical to those observed in aurora-A. Furthermore, overexpression of bora can rescue defects caused by mutations in aurora-A. Bora is conserved in vertebrates, and both Drosophila and human Bora can bind to Aurora-A and activate the kinase in vitro. In interphase cells, Bora is a nuclear protein, but upon entry into mitosis, Bora is excluded from the nucleus and translocates into the cytoplasm in a Cdc2-dependent manner. We propose a model in which activation of Cdc2 initiates the release of Bora into the cytoplasm where it can bind and activate Aurora-A.

  View details for DOI 10.1016/j.devcel.2006.06.002

  View details for PubMedID 16890155

• Wiring stability of the adult Drosophila olfactory circuit after lesion JOURNAL OF NEUROSCIENCE Berdnik, D., Chihara, T., Couto, A., Luo, L. Q. 2006; 26 (13): 3367-3376

  Abstract

  Neuronal wiring plasticity in response to experience or injury has been reported in many parts of the adult nervous system. For instance, visual or somatosensory cortical maps can reorganize significantly in response to peripheral lesions, yet a certain degree of stability is essential for neuronal circuits to perform their dedicated functions. Previous studies on lesion-induced neuronal reorganization have primarily focused on systems that use continuous neural maps. Here, we assess wiring plasticity in a discrete neural map represented by the adult Drosophila olfactory circuit. Using conditional expression of toxins, we genetically ablated specific classes of neurons and examined the consequences on their synaptic partners or neighboring classes in the adult antennal lobe. We find no alteration of connection specificity between olfactory receptor neurons (ORNs) and their postsynaptic targets, the projection neurons (PNs). Ablating an ORN class maintains PN dendrites within their glomerular borders, and ORN axons normally innervating an adjacent target do not expand. Likewise, ablating PN classes does not alter their partner ORN axon connectivity. Interestingly, an increase in the contralateral ORN axon terminal density occurs in response to the removal of competing ipsilateral ORNs. Therefore, plasticity in this circuit can occur but is confined within a glomerulus, thereby retaining the wiring specificity of ORNs and PNs. We conclude that, although adult olfactory neurons can undergo plastic changes in response to the loss of competition, the olfactory circuit overall is extremely stable in preserving segregated information channels in this discrete map.

  View details for DOI 10.1523/JNEUROSCI.4941-05.2006

  View details for Web of Science ID 000236363400001

  View details for PubMedID 16571743

• Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe NATURE NEUROSCIENCE Zhu, H. T., Hummel, T., Clemens, J. C., Berdnik, D., Zipursky, S. L., Luo, L. Q. 2006; 9 (3): 349-355

  Abstract

  In the olfactory system of Drosophila melanogaster, axons of olfactory receptor neurons (ORNs) and dendrites of second-order projection neurons typically target 1 of approximately 50 glomeruli. Dscam, an immunoglobulin superfamily protein, acts in ORNs to regulate axon targeting. Here we show that Dscam acts in projection neurons and local interneurons to control the elaboration of dendritic fields. The removal of Dscam selectively from projection neurons or local interneurons led to clumped dendrites and marked reduction in their dendritic field size. Overexpression of Dscam in projection neurons caused dendrites to be more diffuse during development and shifted their relative position in adulthood. Notably, the positional shift of projection neuron dendrites caused a corresponding shift of its partner ORN axons, thus maintaining the connection specificity. This observation provides evidence for a pre- and postsynaptic matching mechanism independent of precise glomerular positioning.

  View details for Web of Science ID 000235645600014

  View details for PubMedID 16474389

• Quantitative analysis of protein dynamics during asymmetric cell division CURRENT BIOLOGY Mayer, B., Emery, G., Berdnik, D., Wirtz-Peitz, F., Knoblich, J. A. 2005; 15 (20): 1847-1854

  Abstract

  In dividing Drosophila sensory organ precursor (SOP) cells, the fate determinant Numb and its associated adaptor protein Pon localize asymmetrically and segregate into the anterior daughter cell, where Numb influences cell fate by repressing Notch signaling. Asymmetric localization of both proteins requires the protein kinase aPKC and its substrate Lethal (2) giant larvae (Lgl). Because both Numb and Pon localization require actin and myosin, lateral transport along the cell cortex has been proposed as a possible mechanism for their asymmetric distribution. Here, we use quantitative live analysis of GFP-Pon and Numb-GFP fluorescence and fluorescence recovery after photobleaching (FRAP) to characterize the dynamics of Numb and Pon localization during SOP division. We demonstrate that Numb and Pon rapidly exchange between a cytoplasmic pool and the cell cortex and that preferential recruitment from the cytoplasm is responsible for their asymmetric distribution during mitosis. Expression of a constitutively active form of aPKC impairs membrane recruitment of GFP-Pon. This defect can be rescued by coexpression of nonphosphorylatable Lgl, indicating that Lgl is the main target of aPKC. We propose that a high-affinity binding site is asymmetrically distributed by aPKC and Lgl and is responsible for asymmetric localization of cell-fate determinants during mitosis.

  View details for DOI 10.1016/j.cub.2005.08.067

  View details for Web of Science ID 000233110100024

  View details for PubMedID 16243032

• Asymmetric Rab11 endosomes regulate delta recycling and specify cell fate in the Drosophila nervous system CELL Emery, G., Hutterer, A., Berdnik, D., Mayer, B., Wirtz-Peitz, F., Gaitan, M. G., Knoblich, J. A. 2005; 122 (5): 763-773

  Abstract

  Drosophila sensory organ precursor (SOP) cells are a well-studied model system for asymmetric cell division. During SOP division, the determinants Numb and Neuralized segregate into the pIIb daughter cell and establish a distinct cell fate by regulating Notch/Delta signaling. Here, we describe a Numb- and Neuralized-independent mechanism that acts redundantly in cell-fate specification. We show that trafficking of the Notch ligand Delta is different in the two daughter cells. In pIIb, Delta passes through the recycling endosome which is marked by Rab 11. In pIIa, however, the recycling endosome does not form because the centrosome fails to recruit Nuclear fallout, a Rab 11 binding partner that is essential for recycling endosome formation. Using a mammalian cell culture system, we demonstrate that recycling endosomes are essential for Delta activity. Our results suggest that cells can regulate signaling pathways and influence their developmental fate by inhibiting the formation of individual endocytic compartments.

  View details for DOI 10.1016/j.cell.2005.08.017

  View details for Web of Science ID 000231844300015

  View details for PubMedID 16137758

• Localization-dependent and -independent roles of numb contribute to cell-fate specification in Drosophila. Current biology : CB Bhalerao, S., Berdnik, D., Török, T., Knoblich, J. A. 2005; 15 (17): 1583-90

  Abstract

  During asymmetric cell division, protein determinants are segregated into one of the two daughter cells. The Numb protein acts as a segregating determinant during both mouse and Drosophila development. In flies, Numb localizes asymmetrically and is required for cell-fate specification in the central and peripheral nervous systems, as well as during muscle and heart development. Whether its asymmetric segregation is important to the performance of these functions is not firmly established. Here, we demonstrate that Numb acts both in a localization-dependent and in a localization-independent manner. We have generated numb mutants that affect only the asymmetric localization of the protein during mitosis. We demonstrate that asymmetric segregation of Numb into one of the two daughter cells is absolutely essential for cell-fate specification in the Drosophila peripheral nervous system. Numb localization is also essential in MP2 neuroblasts in the central nervous system and during muscle development. Surprisingly, in dividing ganglion mother cells or during heart development, Numb function is independent of its ability to segregate asymmetrically in mitosis. Our results suggest that two classes of asymmetric cell division exist, each with different requirements for asymmetric inheritance of cell-fate determinants.

  View details for DOI 10.1016/j.cub.2005.07.061

  View details for PubMedID 16139215

• Development of wiring specificity of the Drosophila olfactory system Joint Meeting of the 14th International Symposium on Olfaction and Taste/38th Annual Meeting of the Japanese-Association-for-the-Study-of-Taste-and-Smell Jefferis, G. S., Marin, E. C., Komiyama, T., Zhu, H. T., Chihara, T., Berdnik, D., Luo, L. Q. OXFORD UNIV PRESS. 2005: I94–I94

  View details for Web of Science ID 000227615800047

  View details for PubMedID 15738213

• Developmental origin of wiring specificity in the olfactory system of Drosophila DEVELOPMENT Jefferis, G. S., Vyas, R. M., Berdnik, D., Ramaekers, A., Stocker, R. F., Tanaka, N. K., Ito, K., Luo, L. Q. 2004; 131 (1): 117-130

  Abstract

  In both insects and mammals, olfactory receptor neurons (ORNs) expressing specific olfactory receptors converge their axons onto specific glomeruli, creating a spatial map in the brain. We have previously shown that second order projection neurons (PNs) in Drosophila are prespecified by lineage and birth order to send their dendrites to one of approximately 50 glomeruli in the antennal lobe. How can a given class of ORN axons match up with a given class of PN dendrites? Here, we examine the cellular and developmental events that lead to this wiring specificity. We find that, before ORN axon arrival, PN dendrites have already created a prototypic map that resembles the adult glomerular map, by virtue of their selective dendritic localization. Positional cues that create this prototypic dendritic map do not appear to be either from the residual larval olfactory system or from glial processes within the antennal lobe. We propose instead that this prototypic map might originate from both patterning information external to the developing antennal lobe and interactions among PN dendrites.

  View details for DOI 10.1242/dev.00896

  View details for Web of Science ID 000188553900012

  View details for PubMedID 14645123

• The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. Developmental cell Berdnik, D., Török, T., González-Gaitán, M., Knoblich, J. A. 2002; 3 (2): 221-31

  Abstract

  During asymmetric cell division in Drosophila sensory organ precursor cells, the Numb protein localizes asymmetrically and segregates into one daughter cell, where it influences cell fate by repressing signal transduction via the Notch receptor. We show here that Numb acts by polarizing the distribution of alpha-Adaptin, a protein involved in receptor-mediated endocytosis. alpha-Adaptin binds to Numb and localizes asymmetrically in a Numb-dependent fashion. Mutant forms of alpha-Adaptin that no longer bind to Numb fail to localize asymmetrically and cause numb-like defects in asymmetric cell division. Our results suggest a model in which Numb influences cell fate by downregulating Notch through polarized receptor-mediated endocytosis, since Numb also binds to the intracellular domain of Notch.

  View details for DOI 10.1016/s1534-5807(02)00215-0

  View details for PubMedID 12194853

• Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Current biology : CB Berdnik, D., Knoblich, J. A. 2002; 12 (8): 640-7

  Abstract

  During asymmetric cell division in the Drosophila nervous system, Numb segregates into one of two daughter cells where it is required for the establishment of the correct cell fate. Numb is uniformly cortical in interphase, but in late prophase, the protein concentrates in the cortical area overlying one of two centrosomes in an actin/myosin-dependent manner. What triggers the asymmetric localization of Numb at the onset of mitosis is unclear.We show here that the mitotic kinase Aurora-A is required for the asymmetric localization of Numb. In Drosophila sensory organ precursor (SOP) cells mutant for the aurora-A allele aurA(37), Numb is uniformly localized around the cell cortex during mitosis and segregates into both daughter cells, leading to cell fate transformations in the SOP lineage. aurA(37) mutant cells also fail to recruit Centrosomin (Cnn) and gamma-Tubulin to centrosomes during mitosis, leading to spindle morphology defects. However, Numb still localizes asymmetrically in cnn mutants or after disruption of microtubules, indicating that there are two independent functions for Aurora-A in centrosome maturation and asymmetric protein localization during mitosis. Using photobleaching of a GFP-Aurora fusion protein, we show that two rapidly exchanging pools of Aurora-A are present in the cytoplasm and at the centrosome and might carry out these two functions.Our results suggest that activation of the Aurora-A kinase at the onset of mitosis is required for the actin-dependent asymmetric localization of Numb. Aurora-A is also involved in centrosome maturation and spindle assembly, indicating that it regulates both actin- and microtubule-dependent processes in mitotic cells.

  View details for DOI 10.1016/s0960-9822(02)00766-2

  View details for PubMedID 11967150

• Dcas is required for importin-alpha3 nuclear export and mechano-sensory organ cell fate specification in Drosophila. Developmental biology Tekotte, H., Berdnik, D., Török, T., Buszczak, M., Jones, L. M., Cooley, L., Knoblich, J. A., Davis, I. 2002; 244 (2): 396-406

  Abstract

  We have studied the in vivo function and tissue specificity of Dcas, the Drosophila ortholog of CAS, the importin beta-like export receptor for importin alpha. While dcas mRNA is specifically expressed in the embryonic central nervous system, Dcas protein is maternally supplied to all embryonic cells and its nuclear/cytoplasmic distribution varies in different tissues and times in development. Unexpectedly, hypomorphic alleles of dcas show specific transformations in mechano-sensory organ cell identity, characteristic of mutations that increase Notch signaling. Dcas is essential for efficient importin-alpha3 nuclear export in mechano-sensory cells and the surrounding epidermal cells and is indirectly required for the import of one component of the Notch pathway, but not others tested. We interpret the specificity of the dcas phenotype as indicating that one or more Notch signaling components are particularly sensitive to a disruption in nuclear protein import. We propose that mutations in house keeping genes often cause specific developmental phenotypes, such as those observed in many human genetic disorders.

  View details for DOI 10.1006/dbio.2002.0612

  View details for PubMedID 11944946

• Growth phase-regulated induction of Salmonella-induced macrophage apoptosis correlates with transient expression of SPI-1 genes. Journal of bacteriology Lundberg, U., Vinatzer, U., Berdnik, D., von Gabain, A., Baccarini, M. 1999; 181 (11): 3433-7

  Abstract

  Invasive Salmonella has been reported to induce apoptosis in a fraction of infected macrophages within 2 to 14 h from the time of infection by a mechanism involving the type III secretion machinery encoded by the Salmonella pathogenicity island 1 (SPI-1). Here, we show that bacteria in the transition from logarithmic to stationary phase cause 90% of the macrophages to undergo phagocytosis-independent, caspase-mediated apoptosis within 30 to 60 min of infection. The ability of Salmonella to induce this rapid apoptosis was growth phase regulated and cell type restricted, with epithelial cells being resistant. Apoptosis induction was also abrogated by disruption of the hilA gene (encoding a regulator of SPI-1 genes) and by the expression of a constitutively active PhoPQ. hilA itself and a subset of SPI-1 genes were transiently expressed during aerobic growth in liquid medium. Interestingly, however, hilA was found to be required only for the expression of the prgH gene, while sipB, invA, and invF were expressed in a hilA-independent manner. The expression of SPI-1 genes and the secretion of invasion-associated proteins correlated temporally with the induction of apoptosis and are likely to represent its molecular basis. Thus, growth phase transition regulates the expression and secretion of virulence determinants and represents the most efficient environmental cue for apoptosis induction reported to date.

  View details for DOI 10.1128/JB.181.11.3433-3437.1999

  View details for PubMedID 10348855

  View details for PubMedCentralID PMC93810