Deepening the Understanding of CNVs on Chromosome 15q11-13 by Using HiPSCs: An Overview

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2023 Jan 23

PMID 36684422

Authors

Angela Maria Giada Giovenale

Giorgia Ruotolo

Amata Amy Soriano

Elisa Maria Turco

Giovannina Rotundo

Alessia Casamassa

Angela DAnzi

Angelo Luigi Vescovi

Jessica Rosati

Affiliations

Soon will be listed here.

Abstract

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is widely expressed in the central and peripheral nervous systems. This receptor is implicated in both brain development and adult neurogenesis thanks to its ability to mediate acetylcholine stimulus (Ach). Copy number variations (CNVs) of CHRNA7 gene have been identified in humans and are genetically linked to cognitive impairments associated with multiple disorders, including schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, and others. Currently, α7 receptor analysis has been commonly performed in animal models due to the impossibility of direct investigation of the living human brain. But the use of model systems has shown that there are very large differences between humans and mice when researchers must study the CNVs and, in particular, the CNV of chromosome 15q13.3 where the CHRNA7 gene is present. In fact, human beings present genomic alterations as well as the presence of genes of recent origin that are not present in other model systems as well as they show a very heterogeneous symptomatology that is associated with both their genetic background and the environment where they live. To date, the induced pluripotent stem cells, obtained from patients carrying CNV in CHRNA7 gene, are a good model for studying the association of the α7 receptor to human diseases. In this review, we will outline the current state of hiPSCs technology applications in neurological diseases caused by CNVs in CHRNA7 gene. Furthermore, we will discuss some weaknesses that emerge from the overall analysis of the published articles.

References

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

Liu H, Ye Z, Kim Y, Sharkis S, Jang Y . Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology. 2010; 51(5):1810-9. PMC: 2925460. DOI: 10.1002/hep.23626. View

Wisniowiecka-Kowalnik B, Kastory-Bronowska M, Bartnik M, Derwinska K, Dymczak-Domini W, Szumbarska D . Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. Eur J Hum Genet. 2012; 21(6):620-5. PMC: 3658201. DOI: 10.1038/ejhg.2012.219. View

Szatkiewicz J, ODushlaine C, Chen G, Chambert K, Moran J, Neale B . Copy number variation in schizophrenia in Sweden. Mol Psychiatry. 2014; 19(7):762-73. PMC: 4271733. DOI: 10.1038/mp.2014.40. View

Pettigrew K, Reeves E, Leavett R, Hayiou-Thomas M, Sharma A, Simpson N . Copy Number Variation Screen Identifies a Rare De Novo Deletion at Chromosome 15q13.1-13.3 in a Child with Language Impairment. PLoS One. 2015; 10(8):e0134997. PMC: 4532445. DOI: 10.1371/journal.pone.0134997. View

Williams D, Wang J, Papke R . Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states. Mol Pharmacol. 2011; 80(6):1013-32. PMC: 3228536. DOI: 10.1124/mol.111.074302. View

Gillentine M, Schaaf C . The human clinical phenotypes of altered CHRNA7 copy number. Biochem Pharmacol. 2015; 97(4):352-362. PMC: 4600432. DOI: 10.1016/j.bcp.2015.06.012. View

Lewis A, Pittenger S, Mineur Y, Stout D, Smith P, Picciotto M . Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors. Neuropsychopharmacology. 2017; 43(6):1267-1275. PMC: 5916354. DOI: 10.1038/npp.2017.276. View

Guy B, Zhang J, Duncan L, Johnston Jr R . Human neural organoids: Models for developmental neurobiology and disease. Dev Biol. 2021; 478:102-121. PMC: 8364509. DOI: 10.1016/j.ydbio.2021.06.012. View

10.

Bacchelli E, Battaglia A, Cameli C, Lomartire S, Tancredi R, Thomson S . Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility. Am J Med Genet A. 2015; 167A(4):715-23. DOI: 10.1002/ajmg.a.36847. View

11.

Li Y, Muffat J, Omer A, Bosch I, Lancaster M, Sur M . Induction of Expansion and Folding in Human Cerebral Organoids. Cell Stem Cell. 2017; 20(3):385-396.e3. PMC: 6461394. DOI: 10.1016/j.stem.2016.11.017. View

12.

Zhang J, Yao W, Ren Q, Yang C, Dong C, Ma M . Depression-like phenotype by deletion of α7 nicotinic acetylcholine receptor: Role of BDNF-TrkB in nucleus accumbens. Sci Rep. 2016; 6:36705. PMC: 5099687. DOI: 10.1038/srep36705. View

13.

Li R, Sun L, Fang A, Li P, Wu Q, Wang X . Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease. Protein Cell. 2017; 8(11):823-833. PMC: 5676597. DOI: 10.1007/s13238-017-0479-2. View

14.

Lin Y, Seo J, Gao F, Feldman H, Wen H, Penney J . APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018; 98(6):1141-1154.e7. PMC: 6023751. DOI: 10.1016/j.neuron.2018.05.008. View

15.

Tuzun E, Sharp A, Bailey J, Kaul R, Morrison V, Pertz L . Fine-scale structural variation of the human genome. Nat Genet. 2005; 37(7):727-32. DOI: 10.1038/ng1562. View

16.

Gillentine M, Yin J, Bajic A, Zhang P, Cummock S, Kim J . Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells. Am J Hum Genet. 2017; 101(6):874-887. PMC: 5812918. DOI: 10.1016/j.ajhg.2017.09.024. View

17.

Hurst R, Rollema H, Bertrand D . Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2012; 137(1):22-54. DOI: 10.1016/j.pharmthera.2012.08.012. View

18.

Vijayaraghavan S, Pugh P, Zhang Z, Rathouz M, Berg D . Nicotinic receptors that bind alpha-bungarotoxin on neurons raise intracellular free Ca2+. Neuron. 1992; 8(2):353-62. DOI: 10.1016/0896-6273(92)90301-s. View

19.

Marks M, Collins A . Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate. Mol Pharmacol. 1982; 22(3):554-64. View

20.

Gill J, Chatzidaki A, Ursu D, Sher E, Millar N . Contrasting properties of α7-selective orthosteric and allosteric agonists examined on native nicotinic acetylcholine receptors. PLoS One. 2013; 8(1):e55047. PMC: 3558472. DOI: 10.1371/journal.pone.0055047. View