المؤلفون: Donnelly, CG, Burns, E, Easton‐Jones, CA, Katzman, S, Stuart, R, Cook, SE, Finno, CJ

المصدر: Equine Veterinary Education. 33(4)

مصطلحات موضوعية: Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Clinical Research, Prevention, Nutrition, Complementary and Integrative Health, Clinical Trials and Supportive Activities, horse, vitamin E, alpha-tocopherol, Veterinary sciences

الوصف: Vitamin E is essential for neuromuscular function. The primary treatment, oral supplementation with natural ('RRR') α-tocopherol, is not effective in all horses. The objectives of this pilot study were to evaluate the safety and efficacy of a subcutaneously administered RRR-α-tocopherol preparation. Horses were randomly assigned in a cross-over design to initially receive RRR-α-tocopherol (5000 IU/450 kg of 600 IU/mL) subcutaneously (n = 3) or orally (n = 3) or were untreated sentinels (n = 2). Tissue reactions following injection in Phase I of the study necessitated adjustment of the preparation with reduction of the RRR-α-tocopherol concentration to 500 IU/mL in Phase 2. Following an 8-week washout period, horses received the reciprocal treatment route with the new preparation (5000 IU/450 kg of 500 IU/mL). Serum, CSF and muscle α-tocopherol concentrations were determined by high-performance liquid chromatography over a 14-day period during each phase. Serum and CSF α-tocopherol concentrations increased significantly postinjection only when the 500 IU/mL product was administered (P

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/85z2d0d8Test

المؤلفون: Finno, CJ, Estell, KE, Katzman, S, Winfield, L, Rendahl, A, Textor, J, Bannasch, DL, Puschner, B

المصدر: Journal of Veterinary Internal Medicine. 29(6)

مصطلحات موضوعية: Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Neurosciences, Complementary and Integrative Health, Brain Disorders, Animals, Animals, Newborn, Female, Genetic Predisposition to Disease, Horse Diseases, Horses, Male, Neuroaxonal Dystrophies, Selenium, alpha-Tocopherol, Ataxia, Equine, Genetics, Vitamin E, Veterinary sciences

الوصف: BackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α-tocopherol (α-TP)-deficient diet.ObjectiveIntramuscular α-TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α-TP in healthy foals. Serum and CSF α-TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life.AnimalsFourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α-TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals.MethodsComplete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed.ResultsSignificant decreases in blood, CSF α-TP and Se found in the first year of life in all foals, with most significant changes in serum α-TP from 4-150 days. Dam α-TP and Se significantly influenced blood concentrations in foals. Injection of α-TP and Se did not significantly increase CSF Se, blood or CSF α-TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF α-TP through 120 days.Conclusions and clinical importanceInjection of α-TP and Se at 4 days of age does not significantly increase blood or CSF α-TP. Despite all 14 foals remaining deficient in α-TP, only the 4 genetically predisposed foals developed NAD/EDM.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1gw2j205Test

المؤلفون: Burns, E. N., Bordbari, M. H., Mienaltowski, M. J., Affolter, V. K., Barro, M. V., Gianino, F., Gianino, G., Giulotto, E., Kalbfleisch, T. S., Katzman, S. A., Lassaline, M., Leeb, T., Mack, M., Müller, E. J., MacLeod, J. N., Ming‐Whitfield, B., Alanis, C. R., Raudsepp, T., Scott, E., Vig, S., Zhou, H., Petersen, J. L., Bellone, R. R., Finno, C. J.

المساهمون: U.S. Department of Agriculture, National Institute of Food and Agriculture, National Center for Advancing Translational Sciences, NIH Office of the Director

المصدر: Animal Genetics ; volume 49, issue 6, page 564-570 ; ISSN 0268-9146 1365-2052

الوصف: Summary The Functional Annotation of Animal Genomes ( FAANG ) project aims to identify genomic regulatory elements in both sexes across multiple stages of development in domesticated animals. This study represents the first stage of the FAANG project for the horse, Equus caballus . A biobank of 80 tissue samples, two cell lines and six body fluids was created from two adult Thoroughbred mares. Ante‐mortem assessments included full physical examinations, lameness, ophthalmologic and neurologic evaluations. Complete blood counts and serum biochemistries were also performed. At necropsy, in addition to tissue samples, aliquots of serum, ethylenediaminetetraacetic acid (EDTA) plasma, heparinized plasma, cerebrospinal fluid, synovial fluid, urine and microbiome samples from all regions of the gastrointestinal and urogenital tracts were collected. Epidermal keratinocytes and dermal fibroblasts were cultured from skin samples. All tissues were grossly and histologically evaluated by a board‐certified veterinary pathologist. The results of the clinical and pathological evaluations identified subclinical eosinophilic and lymphocytic infiltration throughout the length of the gastrointestinal tract as well as a mild clinical lameness in both animals. Each sample was cryo‐preserved in multiple ways, and nuclei were extracted from selected tissues. These samples represent the first published systemically healthy equine‐specific biobank with extensive clinical phenotyping ante ‐ and post‐mortem . The tissues in the biobank are intended for community‐wide use in the functional annotation of the equine genome. The use of the biobank will improve the quality of the reference annotation and allow all equine researchers to elucidate unknown genomic and epigenomic causes of disease.

الإتاحة: https://doi.org/10.1111/age.12717Test

المؤلفون: Tranah, G.J., Katzman, S., Cummings, S.R.

المصدر: Innovation in Aging ; volume 1, issue suppl_1, page 858-859 ; ISSN 2399-5300

الإتاحة: https://doi.org/10.1093/geroni/igx004.3089Test
http://academic.oup.com/innovateage/article-pdf/1/suppl_1/858/26124058/igx004.3089.pdfTest

المؤلفون: Donnelly C. G., Bellone R. R., Hales E. N., Nguyen A., Katzman S. A., Dujovne G. A., Knickelbein K. E., Avila F., Kalbfleisch T. S., Giulotto E., Kingsley N. B., Tanaka J., Esdaile E., Peng S., Dahlgren A., Fuller A., Mienaltowski M. J., Raudsepp T., Affolter V. K., Petersen J. L., Finno C. J.

المساهمون: Donnelly, C. G., Bellone, R. R., Hales, E. N., Nguyen, A., Katzman, S. A., Dujovne, G. A., Knickelbein, K. E., Avila, F., Kalbfleisch, T. S., Giulotto, E., Kingsley, N. B., Tanaka, J., Esdaile, E., Peng, S., Dahlgren, A., Fuller, A., Mienaltowski, M. J., Raudsepp, T., Affolter, V. K., Petersen, J. L., Finno, C. J.

مصطلحات موضوعية: biobank, FAANG, horse, male, stallion

الوصف: Following the successful creation of a biobank from two adult Thoroughbred mares, this study aimed to recapitulate sample collection in two adult Thoroughbred stallions as part of the Functional Annotation of the Animal Genome (FAANG) initiative. Both stallions underwent thorough physical, lameness, neurologic, and ophthalmic (including electroretinography) examinations prior to humane euthanasia. Epididymal sperm was recovered from both stallions immediately postmortem and cryopreserved. Aseptically collected full thickness skin biopsies were used to isolate, culture and cryopreserve dermal fibroblasts. Serum, plasma, cerebrospinal fluid, urine, and gastrointestinal content from various locations were collected and cryopreserved. Under guidance of a board-certified veterinary anatomic pathologist, 102 representative tissue samples were collected from both horses. Whole tissue samples were flash-frozen and prioritized tissues had nuclei isolated and cryopreserved. Spatially contemporaneous samples of each tissue were submitted for histologic examination. Antemortem and gross pathologic examination revealed mild abnormalities in both stallions. One stallion (ECA_UCD_AH3) had unilateral thoracic limb lameness and bilateral chorioretinal scars. The second stallion (ECA_UCD_AH4) had subtle symmetrical pelvic limb ataxia, symmetrical prostatomegally, and moderate gastrointestinal nematodiasis. DNA from each was whole-genome sequenced and genotyped using the GGP Equine 70K SNP array. The genomic resources and banked biological samples from these animals augments the existing resource available to the equine genomics community. Importantly we may now improve the resolution of tissue-specific gene regulation as affected by sex, as well as add sex-specific tissues and gametes.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33763124; info:eu-repo/semantics/altIdentifier/wos/WOS:000631054600001; volume:12; firstpage:650305; journal:FRONTIERS IN GENETICS; http://hdl.handle.net/11571/1449901Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85102928831; https://www.frontiersin.org/articles/10.3389/fgene.2021.650305/fullTest

الإتاحة: https://doi.org/10.3389/fgene.2021.650305Test
http://hdl.handle.net/11571/1449901Test

المؤلفون: Finno, C. J., Estell, Krista, Katzman, S., Winfield, L., Rendahl, A., Textor, J., Bannasch, D. L., Puschner, B.

مصطلحات موضوعية: Ataxia, Equine, Genetics, Vitamin E, Animals, Newborn, Female, Genetic Predisposition to Disease, Horse Diseases, Horses, Male, Neuroaxonal Dystrophies, Selenium, alpha-Tocopherol

جغرافية الموضوع: United States

الوصف: BACKGROUND: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on -tocopherol (-TP)-deficient diet. OBJECTIVE: Intramuscular -TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) -TP in healthy foals. Serum and CSF -TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life. ANIMALS: Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable -TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals. METHODS: Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed. RESULTS: Significant decreases in blood, CSF -TP and Se found in the first year of life in all foals, with most significant changes in serum -TP from 4-150 days. Dam -TP and Se significantly influenced blood concentrations in foals. Injection of -TP and Se did not significantly increase CSF Se, blood or CSF -TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF -TP through 120 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Injection of -TP and Se at 4 days of age does not significantly increase blood or CSF -TP. Despite all 14 foals remaining deficient in -TP, only the 4 genetically predisposed foals developed NAD/EDM. ; Published version

وصف الملف: 1667 - 1675 page(s); application/pdf

العلاقة: http://www.ncbi.nlm.nih.gov/pubmed/26391904Test; http://hdl.handle.net/10919/77598Test; https://doi.org/10.1111/jvim.13618Test; 29; Estell, KE [0000-0002-9321-1952]

الإتاحة: https://doi.org/10.1111/jvim.13618Test
http://hdl.handle.net/10919/77598Test

المؤلفون: Brat D. J., Verhaak R. G. W., Aldape K. D., Yung W. K. A., Salama S. R., Cooper L. A. D., Rheinbay E., Miller C. R., Vitucci M., Morozova O., Robertson A. G., Noushmehr H., Laird P. W., Cherniack A. D., Akbani R., Huse J. T., Ciriello G., Poisson L. M., Barnholtz-Sloan J. S., Berger M. S., Brennan C., Colen R. R., Colman H., Flanders A. E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B. A., O'Neill B. P., Pachter L., Parsons D. W., Sougnez C., Sulman E. P., Vandenberg S. R., Van Meir E. G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K. M., Lichtenberg T. M., Pierson C. R., Ramirez N. C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J. A., Eley G., Ferguson M. L., Hutter C. M., Shaw K. R. M., Ozenberger B. A., Sheth M., Sofia H. J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J. C., Ayala B., Baboud J., Chudamani S., Jensen M. A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J. T., Balasundaram M., Balu S., Baylin S. B., Beroukhim R., Bootwalla M. S., Bowlby R., Bristow C. A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A., Chuah E., Cibulskis K., Clarke A., Coetzee S. G., Dhalla N., Fennell T., Fisher S., Gabriel S., Getz G., Gibbs R., Guin R., Hadjipanayis A., Hayes D. N., Hinoue T., Hoadley K., Holt R. A., Hoyle A. P., Jefferys S. R., Jones S., Jones C. D., Kucherlapati R., Lai P. H., Lander E., Lee S., Lichtenstein L., Ma Y., Maglinte D. T., Mahadeshwar H. S., Marra M. A., Mayo M., Meng S., Meyerson M. L., Mieczkowski P. A., Moore R. A., Mose L. E., Mungall A. J., Pantazi A., Parfenov M., Park P. J., Parker J. S., Perou C. M., Protopopov A., Ren X., Roach J., Sabedot T. S., Schein J., Schumacher S. E., Seidman J. G., Seth S., Shen H., Simons J. V., Sipahimalani P., Soloway M. G., Song X., Sun H., Tabak B., Tam A., Tan D., Tang J., Thiessen N., Triche T., Van Den Berg D. J., Veluvolu U., Waring S., Weisenberger D. J., Wilkerson M. D., Wong T., Wu J., Xi L., Xu A. W., Zack T. I., Zhang J., Aksoy B. A., Arachchi H., Benz C., Bernard B., Carlin D., Cho J., DiCara D., Frazer S., Fuller G. N., Gao J., Gehlenborg N., Haussler D., Heiman D. I., Iype L., Jacobsen A., Ju Z., Katzman S., Kim H., Knijnenburg T., Kreisberg R. B., Lawrence M. S., Lee W., Leinonen K., Lin P., Ling S., Liu W., Liu Y., Lu Y., Mills G., Ng S., Noble M. S., Paull E., Rao A., Reynolds S., Saksena G., Sanborn Z., Sander C., Schultz N., Senbabaoglu Y., Shen R., Shmulevich I., Sinha R., Stuart J., Sumer S. O., Sun Y., Tasman N., Taylor B. S., Voet D., Weinhold N., Weinstein J. N., Yang D., Yoshihara K., Zheng S., Zhang W., Zou L., Abel T., Sadeghi S., Cohen M. L., Eschbacher J., Hattab E. M., Raghunathan A., Schniederjan M. J., Aziz D., Barnett G., Barrett W., Bigner D. D., Boice L., Brewer C., Calatozzolo C., Campos B., Carlotti C. G., Chan T. A., Cuppini L., Curley E., Cuzzubbo S., Devine K., DiMeco F., Duell R., Elder J. B., Fehrenbach A., Finocchiaro G., Friedman W., Fulop J., Gardner J., Hermes B., Herold-Mende C., Jungk C., Kendler A., Lehman N. L., Lipp E., Liu O., Mandt R., McGraw M., Mclendon R., McPherson C., Neder L., Nguyen P., Noss A., Nunziata R., Ostrom Q. T., Palmer C., Perin A., Pollo B., Potapov A., Potapova O., Rathmell W. K., Rotin D., Scarpace L., Schilero C., Senecal K., Shimmel K., Shurkhay V., Sifri S., Singh R., Sloan A. E., Smolenski K., Staugaitis S. M., Steele R., Thorne L., Tirapelli D. P. C., Unterberg A., Vallurupalli M., Wang Y., Warnick R., Williams F., Wolinsky Y., Bell S., Rosenberg M., Stewart C., Huang F., Grimsby J. L., Radenbaugh A. J.

المساهمون: Brat D.J., Verhaak R.G.W., Aldape K.D., Yung W.K.A., Salama S.R., Cooper L.A.D., Rheinbay E., Miller C.R., Vitucci M., Morozova O., Robertson A.G., Noushmehr H., Laird P.W., Cherniack A.D., Akbani R., Huse J.T., Ciriello G., Poisson L.M., Barnholtz-Sloan J.S., Berger M.S., Brennan C., Colen R.R., Colman H., Flanders A.E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B.A., O'Neill B.P., Pachter L., Parsons D.W., Sougnez C., Sulman E.P., Vandenberg S.R., Van Meir E.G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K.M., Lichtenberg T.M., Pierson C.R., Ramirez N.C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J.A., Eley G., Ferguson M.L., Hutter C.M., Shaw K.R.M., Ozenberger B.A., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Ayala B., Baboud J., Chudamani S., Jensen M.A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J.T., Balasundaram M., Balu S., Baylin S.B., Beroukhim R., Bootwalla M.S., Bowlby R., Bristow C.A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A.

مصطلحات موضوعية: Adolescent, Adult, Aged, Chromosomes, Human, Pair 1, Pair 19, Cluster Analysi, DNA, Neoplasm, Female, Glioblastoma, Glioma, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Grading, Proportional Hazards Model, Sequence Analysis, Signal Transduction, Genes, p53, Mutation

الوصف: BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade ...

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/26061751; info:eu-repo/semantics/altIdentifier/wos/WOS:000356788200005; volume:372; issue:26; firstpage:2481; lastpage:2498; numberofpages:18; journal:NEW ENGLAND JOURNAL OF MEDICINE; http://hdl.handle.net/11585/720448Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84932628860

الإتاحة: https://doi.org/10.1056/NEJMoa1402121Test
http://hdl.handle.net/11585/720448Test

المؤلفون: Donnelly, C. G., Burns, E., Easton‐Jones, C. A., Katzman, S., Stuart, R., Cook, S. E., Finno, C. J.

المساهمون: Stuart Products

المصدر: Equine Veterinary Education ; volume 33, issue 4, page 215-219 ; ISSN 0957-7734 2042-3292

الوصف: Summary Vitamin E is essential for neuromuscular function. The primary treatment, oral supplementation with natural (‘RRR’) α‐tocopherol, is not effective in all horses. The objectives of this pilot study were to evaluate the safety and efficacy of a subcutaneously administered RRR‐α‐tocopherol preparation. Horses were randomly assigned in a cross‐over design to initially receive RRR‐α‐tocopherol (5000 IU/450 kg of 600 IU/mL) subcutaneously (n = 3) or orally (n = 3) or were untreated sentinels (n = 2). Tissue reactions following injection in Phase I of the study necessitated adjustment of the preparation with reduction of the RRR‐α‐tocopherol concentration to 500 IU/mL in Phase 2. Following an 8‐week washout period, horses received the reciprocal treatment route with the new preparation (5000 IU/450 kg of 500 IU/mL). Serum, CSF and muscle α‐tocopherol concentrations were determined by high‐performance liquid chromatography over a 14‐day period during each phase. Serum and CSF α‐tocopherol concentrations increased significantly postinjection only when the 500 IU/mL product was administered (P<0.0001). There was no significant difference in the muscle concentration of α‐tocopherol following either treatment. All eight horses had marked tissue reaction to subcutaneous injection, regardless of product concentration. Whilst we have demonstrated that this route may be a useful alternative to oral supplementation, the marked tissue reaction makes use of such products limited at this time to only the most refractory of cases.

الإتاحة: https://doi.org/10.1111/eve.13308Test

المؤلفون: Katzman, S, Cech, JJ

مصطلحات موضوعية: Journal Articles

وصف الملف: text/html

العلاقة: http://jeb.biologists.org/cgi/content/short/204/10/1711Test

الإتاحة: http://jeb.biologists.org/cgi/content/short/204/10/1711Test

المؤلفون: Fiddes, I.T., Lodewijk, G.A., Mooring, M., Bosworth, C.M., Ewing, A.D., Mantalas, G.L., Novak, A.M., van den Bout, A., Bishara, A., Rosenkrantz, J.L., Lorig-Roach, R., Field, A.R., Haeussler, M., Russo, L., Bhaduri, A., Nowakowski, T.J., Pollen, A.A., Dougherty, M.L., Nuttle, X., Addor, M.C., Zwolinski, S., Katzman, S., Kriegstein, A., Eichler, E.E., Salama, S.R., Jacobs, FMJ, Haussler, D.

المصدر: Cell, vol. 173, no. 6, pp. 1356-1369.e22

مصطلحات موضوعية: Animals, Brain/embryology, Cell Differentiation, Cerebral Cortex/physiology, Embryonic Stem Cells/metabolism, Female, Gene Deletion, Genes, Reporter, Gorilla gorilla, HEK293 Cells, Humans, Neocortex/cytology, Neural Stem Cells/metabolism, Neurogenesis/physiology, Neuroglia/metabolism, Neurons/metabolism, Pan troglodytes, Receptor, Notch2/genetics, Notch2/metabolism, Sequence Analysis, RNA, Signal Transduction, 1q21.1, Notch signaling, autism, cortical organoids, human evolution, neural stem cells

الوصف: Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29856954; info:eu-repo/semantics/altIdentifier/eissn/1097-4172; https://serval.unil.ch/notice/serval:BIB_6AB4448DA6E1Test; urn:issn:0092-8674

الإتاحة: https://doi.org/10.1016/j.cell.2018.03.051Test
https://serval.unil.ch/notice/serval:BIB_6AB4448DA6E1Test