Person: Bernards, Andre
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Bernards
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Andre
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Bernards, Andre
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Publication Genetic and Functional Studies Implicate Synaptic Overgrowth and Ring Gland cAMP/PKA Signaling Defects in the Drosophila melanogaster Neurofibromatosis-1 Growth Deficiency(Public Library of Science, 2013) Walker, James; Gouzi, Jean Y.; Long, Jennifer B; Huang, Sidong; Maher, Robert C.; Xia, Hongjing; Khalil, Kheyal; Ray, Arjun; Van Vactor, David; Bernards, René; Bernards, AndreNeurofibromatosis type 1 (NF1), a genetic disease that affects 1 in 3,000, is caused by loss of a large evolutionary conserved protein that serves as a GTPase Activating Protein (GAP) for Ras. Among Drosophila melanogaster Nf1 (dNf1) null mutant phenotypes, learning/memory deficits and reduced overall growth resemble human NF1 symptoms. These and other dNf1 defects are relatively insensitive to manipulations that reduce Ras signaling strength but are suppressed by increasing signaling through the 3′-5′ cyclic adenosine monophosphate (cAMP) dependent Protein Kinase A (PKA) pathway, or phenocopied by inhibiting this pathway. However, whether dNf1 affects cAMP/PKA signaling directly or indirectly remains controversial. To shed light on this issue we screened 486 1st and 2nd chromosome deficiencies that uncover >80% of annotated genes for dominant modifiers of the dNf1 pupal size defect, identifying responsible genes in crosses with mutant alleles or by tissue-specific RNA interference (RNAi) knockdown. Validating the screen, identified suppressors include the previously implicated dAlk tyrosine kinase, its activating ligand jelly belly (jeb), two other genes involved in Ras/ERK signal transduction and several involved in cAMP/PKA signaling. Novel modifiers that implicate synaptic defects in the dNf1 growth deficiency include the intersectin-related synaptic scaffold protein Dap160 and the cholecystokinin receptor-related CCKLR-17D1 drosulfakinin receptor. Providing mechanistic clues, we show that dAlk, jeb and CCKLR-17D1 are among mutants that also suppress a recently identified dNf1 neuromuscular junction (NMJ) overgrowth phenotype and that manipulations that increase cAMP/PKA signaling in adipokinetic hormone (AKH)-producing cells at the base of the neuroendocrine ring gland restore the dNf1 growth deficiency. Finally, supporting our previous contention that ALK might be a therapeutic target in NF1, we report that human ALK is expressed in cells that give rise to NF1 tumors and that NF1 regulated ALK/RAS/ERK signaling appears conserved in man.Publication Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis(Springer Nature, 2015) Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis; Kathiresan, Sekar; Cohen, David E.; Whetstine, Johnathan; Chung, Raymond; Fernández-Hernando, Carlos; Kaplan, Lee; Bernards, Andre; Gerszten, Robert; Naar, AndersGenome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.Publication A Drosophila screen identifies neurofibromatosis-1 genetic modifiers involved in systemic and synaptic growth(Landes Bioscience, 2014) Walker, James; Bernards, AndreNeurofibromatosis type 1 (NF1) is caused by loss of a negative regulator of Ras oncoproteins. Unknown genetic modifiers have been implicated in NF1’s characteristic variability. Drosophila melanogaster dNf1 phenotypes include cognitive deficits and reduced growth, both of which resemble human symptoms. We recently reported results of a screen for dominant modifiers of dNf1 growth. Suppressors include the dAlk tyrosine kinase and its activating ligand, two other genes involved in Ras/ERK signal transduction, the synaptic scaffold Dap160 and the CCKLR-17D1 drosulfakinin receptor. Additional modifiers include several genes involved in cAMP/PKA signaling. Providing mechanistic insights, dAlk, jeb, and CCKLR-17D1 also suppress a dNf1 synaptic overgrowth defect, and increasing cAMP/PKA signaling in the neuroendocrine ring gland rescued the dNf1 growth deficiency. Finally, among the several suppressors identified in our screen, we specifically implicate ALK as a potential therapeutic target by showing that NF1-regulated ALK/RAS/ERK signaling is conserved in human cells.Publication CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies(Wiley-Blackwell, 2014) Widemann, Brigitte C.; Acosta, Maria T.; Ammoun, Sylvia; Belzberg, Allan J.; Bernards, Andre; Blakeley, Jaishri; Bretscher, Antony; Cichowski, Karen; Clapp, D. Wade; Dombi, Eva; Evans, Gareth D.; Ferner, Rosalie; Fernandez-Valle, Cristina; Fisher, Michael J.; Giovannini, Marco; Gutmann, David H.; Hanemann, C. Oliver; Hennigan, Robert; Huson, Susan; Ingram, David; Kissil, Joe; Korf, Bruce R.; Legius, Eric; Packer, Roger J.; McClatchey, Andrea; McCormick, Frank; North, Kathryn; Pehrsson, Minja; Plotkin, Scott; Ramesh, Vijaya; Ratner, Nancy; Schirmer, Susann; Sherman, Larry; Schorry, Elizabeth; Stevenson, David; Stewart, Douglas; Ullrich, Nicole; Bakker, Annette C.; Morrison, HelenThe neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a “state-of-the-field” for NF research in 2012.Publication Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency(2012) Blackburn, Jessica S.; Liu, Sali; Raiser, Dave; Martinez, Sarah A.; Feng, Hui; Meeker, Nathan D.; Gentry, Jeffery; Neuberg, Donna; Look, A.; Ramaswamy, Sridhar; Bernards, Andre; Trede, Nikolaus S.; Langenau, DavidNOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs.Publication Analysis of Somatic Microsatellite Indels Identifies Driver Events in Human Tumors(Springer Science and Business Media LLC, 2017-09-11) Maruvka, Yosef; Mouw, Kent; Karlic, Rosa; Parasuraman, Prasanna; Kamburov, Atanas; Polak, Paz; Haradhvala, Nicholas; Hess, Julian; Rheinbay, Esther; Brody, Yehuda; Koren, Amnon; Braunstein, Lior; D'Andrea, Alan; Lawrence, Michael; Bass, Adam; Bernards, Andre; Michor, Franziska; Getz, GadMicrosatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).Publication Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing(The Rockefeller University Press, 2017) Tang, Qin; Iyer, Sowmya; Lobbardi, Riadh; Moore, John C.; Chen, Huidong; Lareau, Caleb; Hebert, Christine; Shaw, McKenzie L.; Neftel, Cyril; Suva, Mario; Ceol, Craig J.; Bernards, Andre; Aryee, Martin; Pinello, Luca; Drummond, Iain; Langenau, DavidRecent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA–protein kinase catalytic subunit (prkdc), interleukin-2 receptor γ a (il2rga), and double-homozygous–mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish.