Modeling Williams Syndrome with Induced Pluripotent Stem Cells

Overview

Journal Neurogenesis (Austin)

Date 2017 Feb 24

PMID 28229087

Citations 10

Authors

Thanathom Chailangkarn

Alysson R Muotri

Affiliations

Soon will be listed here.

Abstract

The development of induced pluripotent stem cells (iPSCs) like never before has opened novel opportunity to study diseases in relevant cell types. In our recent study, Williams syndrome (WS), a rare genetic neurodevelopmental disorder, that is caused by hemizygous deletion of 25-28 genes on chromosome 7, is of interest because of its unique cognitive and social profiles. Little is known about haploinsufficiency effect of those deleted genes on molecular and cellular phenotypes at the neural level due to the lack of relevant human cellular model. Using the cellular reprogramming approach, we reported that WS iPSC-derived neural progenitor cells (NPCs) has increased apoptosis and therefore increased doubling time, which could be rescued by complementation of frizzled 9, one of the genes typically deleted in WS. Moreover, WS iPSC-derived CTIP2-positive pyramidal neurons exhibit morphologic alterations including longer total dendrites and increasing dendritic spine number. In addition, WS iPSC-derived neurons show an increase in calcium transient frequency and synchronized activity likely due to increased number of dendritic spines and synapses. Our work integrated cross-level data from genetics to behavior of WS individuals and revealed altered cellular phenotypes in WS human NPCs and neurons that could be validated in other model systems such as magnetic resonance imaging (MRI) in live subjects and postmortem brain tissues.

Citing Articles

Disruption of common ocular developmental pathways in patient-derived optic vesicle models of microphthalmia.

Eintracht J, Owen N, Harding P, Moosajee M Stem Cell Reports. 2024; 19(6):839-858.

PMID: 38821055 PMC: 11390689. DOI: 10.1016/j.stemcr.2024.05.001.

Boosting Neurogenesis in the Adult Hippocampus Using Antidepressants and Mesenchymal Stem Cells.

Kot M, Neglur P, Pietraszewska A, Buzanska L Cells. 2022; 11(20).

PMID: 36291101 PMC: 9600461. DOI: 10.3390/cells11203234.

Williams syndrome: reduced orienting to other's eyes in a hypersocial phenotype.

Kleberg J, Riby D, Fawcett C, Bjorlin Avdic H, Frick M, Brocki K J Autism Dev Disord. 2022; 53(7):2786-2797.

PMID: 35445369 PMC: 9020553. DOI: 10.1007/s10803-022-05563-6.

Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via and Modulation.

Grad M, Nir A, Levy G, Trangle S, Shapira G, Shomron N Cells. 2022; 11(1).

PMID: 35011720 PMC: 8750756. DOI: 10.3390/cells11010158.

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering.

Gahwiler E, Motta S, Martin M, Nugraha B, Hoerstrup S, Emmert M Front Cell Dev Biol. 2021; 9:639699.

PMID: 34262897 PMC: 8273765. DOI: 10.3389/fcell.2021.639699.

References

Morris C, Mervis C . Williams syndrome and related disorders. Annu Rev Genomics Hum Genet. 2001; 1:461-84. DOI: 10.1146/annurev.genom.1.1.461. View

Chailangkarn T, Trujillo C, Freitas B, Hrvoj-Mihic B, Herai R, Yu D . A human neurodevelopmental model for Williams syndrome. Nature. 2016; 536(7616):338-43. PMC: 4995142. DOI: 10.1038/nature19067. View

Kim D, Cheriyath V, Roy A, Cochran B . TFII-I enhances activation of the c-fos promoter through interactions with upstream elements. Mol Cell Biol. 1998; 18(6):3310-20. PMC: 108912. DOI: 10.1128/MCB.18.6.3310. View

Merla G, Howald C, Henrichsen C, Lyle R, Wyss C, Zabot M . Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Am J Hum Genet. 2006; 79(2):332-41. PMC: 1559497. DOI: 10.1086/506371. View

Chapman R, Hesketh L . Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev. 2000; 6(2):84-95. DOI: 10.1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P. View

Zhao C, Aviles C, Abel R, Almli C, McQuillen P, Pleasure S . Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval. Development. 2005; 132(12):2917-27. DOI: 10.1242/dev.01871. View

Urban Z, Helms C, Fekete G, Csiszar K, Bonnet D, Munnich A . 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet. 1996; 59(4):958-62. PMC: 1914803. View

Fusco C, Micale L, Augello B, Pellico M, Menghini D, Alfieri P . Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits. Eur J Hum Genet. 2013; 22(1):64-70. PMC: 3865388. DOI: 10.1038/ejhg.2013.101. View

Marchetto M, Carromeu C, Acab A, Yu D, Yeo G, Mu Y . A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010; 143(4):527-39. PMC: 3003590. DOI: 10.1016/j.cell.2010.10.016. View

10.

Li D, Brooke B, Davis E, Mecham R, Sorensen L, Boak B . Elastin is an essential determinant of arterial morphogenesis. Nature. 1998; 393(6682):276-80. DOI: 10.1038/30522. View

11.

Ronald A, Happe F, Bolton P, Butcher L, Price T, Wheelwright S . Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry. 2006; 45(6):691-699. DOI: 10.1097/01.chi.0000215325.13058.9d. View

12.

Kaufmann W, Tierney E, Rohde C, Suarez-Pedraza M, Clarke M, Salorio C . Social impairments in Rett syndrome: characteristics and relationship with clinical severity. J Intellect Disabil Res. 2011; 56(3):233-47. DOI: 10.1111/j.1365-2788.2011.01404.x. View

13.

Caraveo G, van Rossum D, Patterson R, Snyder S, Desiderio S . Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science. 2006; 314(5796):122-5. DOI: 10.1126/science.1127815. View

14.

Young E, Lipina T, Tam E, Mandel A, Clapcote S, Bechard A . Reduced fear and aggression and altered serotonin metabolism in Gtf2ird1-targeted mice. Genes Brain Behav. 2007; 7(2):224-34. PMC: 2883608. DOI: 10.1111/j.1601-183X.2007.00343.x. View

15.

HUTTENLOCHER P . Dendritic development in neocortex of children with mental defect and infantile spasms. Neurology. 1974; 24(3):203-10. DOI: 10.1212/wnl.24.3.203. View

16.

Fujiwara T, Mishima T, Kofuji T, Chiba T, Tanaka K, Yamamoto A . Analysis of knock-out mice to determine the role of HPC-1/syntaxin 1A in expressing synaptic plasticity. J Neurosci. 2006; 26(21):5767-76. PMC: 6675267. DOI: 10.1523/JNEUROSCI.0289-06.2006. View

17.

Curran M, Atkinson D, Ewart A, Morris C, Leppert M, Keating M . The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell. 1993; 73(1):159-68. DOI: 10.1016/0092-8674(93)90168-p. View

18.

Andrade L, Nathanson J, Yeo G, Menck C, Muotri A . Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome. Hum Mol Genet. 2012; 21(17):3825-34. PMC: 3412382. DOI: 10.1093/hmg/dds211. View

19.

Ranheim E, Kwan H, Reya T, Wang Y, Weissman I, Francke U . Frizzled 9 knock-out mice have abnormal B-cell development. Blood. 2004; 105(6):2487-94. DOI: 10.1182/blood-2004-06-2334. View

20.

Frangiskakis J, Ewart A, Morris C, Mervis C, Bertrand J, Robinson B . LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell. 1996; 86(1):59-69. DOI: 10.1016/s0092-8674(00)80077-x. View