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Molecular Neurobiology

, Volume 56, Issue 12, pp 8277–8295 | Cite as

Altered Gene Expression of Thyroid Hormone Transporters and Deiodinases in iPS MeCP2-Knockout Cells-Derived Neurons

  • Janaina Sena de SouzaEmail author
  • Divino Romão Ferreira
  • Roberto Herai
  • Cassiano Carromeu
  • Laila Brito Torres
  • Bruno Henrique Silva Araujo
  • Fernanda Cugola
  • Rui M. B. Maciel
  • Alysson Renato Muotri
  • Gisele Giannocco
Article

Abstract

MeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neuronal progenitor cells and adult neurons. Using this cellular model, we then investigated the expression of genes associated with TH homeostasis, such as the TH transporters (LAT1, LAT2, MCT8, MCT10, and OATP4A1) and deiodinases (DIO1, 2, and 3). Then, we treated the neural cells with THs and analyzed the expression of several genes related to neurodevelopment and functional maintenance. Our results showed that several TH-related genes, such as deiodinases, are altered in RTT samples when compared to WT cells. Moreover, the treatment of the neural cells with THs increased the amount of MAP2 and synapsin-1 expression in RTT cells. Our work provided evidences that TH homeostasis is compromised in RTT-derived neural cells, which could be an important factor to contribute to the imbalance in the neurodevelopmental phenotype presented in this syndrome and can lead us to better understand other neurodevelopmental diseases.

Keywords

MeCP2 gene mutation Rett syndrome Thyroid hormones Gene expression Transporter Deiodinase 

Notes

Acknowledgments

This work was supported by a NARSAD Independent Investigator Grant to A.R.M., and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brasilia, Brazil) 18952-12-7 and Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, São Paulo, Brazil) 2017/07053-3 to J.S.S., and from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, São Paulo, Brazil) 2014/08049-1 to B.H.S.A.

Compliance with Ethical Standards

This study is part of a reviewed and approved research by the UCSD Human Research Protections Program and it is in accordance with requirements of the Code of Federal Regulations on the Protection of Human Subjects (reference number is 090801ZF).

Conflict of Interest

Dr. Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

Supplementary material

12035_2019_1645_MOESM1_ESM.docx (95 kb)
ESM 1 (DOCX 94 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Janaina Sena de Souza
    • 1
    • 2
    Email author
  • Divino Romão Ferreira
    • 1
  • Roberto Herai
    • 3
  • Cassiano Carromeu
    • 2
  • Laila Brito Torres
    • 4
    • 5
  • Bruno Henrique Silva Araujo
    • 6
  • Fernanda Cugola
    • 2
  • Rui M. B. Maciel
    • 1
  • Alysson Renato Muotri
    • 2
  • Gisele Giannocco
    • 1
    • 7
  1. 1.Departamento de Medicina, Laboratório de Endocrinologia e Medicina TranslacionalUniversidade Federal de São Paulo, UNIFESP/EPMSão PauloBrazil
  2. 2.Department of Pediatrics, School of MedicineUniversity of California, San DiegoLa JollaUSA
  3. 3.Graduate Program in Health Sciences, School of MedicinePontifícia Universidade Católica do Paraná (PUCPR/PPGCS)CuritibaBrazil
  4. 4.Faculdade São Leopoldo Mandic, Área de Fisiologia, FarmacologiaInstituto São Leopoldo MandicCampinasBrazil
  5. 5.Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of BiociencesUniversidade de São Paulo (USP)São PauloBrazil
  6. 6.Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM)CampinasBrazil
  7. 7.Departamento de Ciências BiológicasUniversidade Federal de São Paulo, UNIFESPDiademaBrazil

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