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Dyslexia Candidate Gene and Ciliary Gene Expression Dynamics During Human Neuronal Differentiation

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Dyslexia Candidate Gene and Ciliary Gene Expression Dynamics During Human Neuronal Differentiation Dyslexia Candidate Gene and Ciliary Gene Expression Dynamics During Human Neuronal Differentiation Bieder, Andrea; Yoshihara, Masahito; Katayama, Shintaro; Krjutškov, Kaarel; Falk, Anna; Kere, Juha; Tapia-Páez, Isabel Published in: Molecular Neurobiology DOI: 10.1007/s12035-020-01905-6 2020 Document Version: Publisher's PDF, also known as Version of record Link to publication Citation for published version (APA): Bieder, A., Yoshihara, M., Katayama, S., Krjutškov, K., Falk, A., Kere, J., & Tapia-Páez, I. (2020). Dyslexia Candidate Gene and Ciliary Gene Expression Dynamics During Human Neuronal Differentiation. Molecular Neurobiology, 57(7), 2944-2958. https://doi.org/10.1007/s12035-020-01905-6 Total number of authors: 7 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Molecular Neurobiology (2020) 57:2944–2958 https://doi.org/10.1007/s12035-020-01905-6 Dyslexia Candidate Gene and Ciliary Gene Expression Dynamics During Human Neuronal Differentiation Andrea Bieder1 & Masahito Yoshihara1 & Shintaro Katayama1 & Kaarel Krjutškov1,2,3,4 & Anna Falk5 & Juha Kere1,3,4,6 & Isabel Tapia-Páez7 Received: 18 December 2019 /Accepted: 19 March 2020 / Published online: 22 May 2020 # The Author(s) 2020 Abstract Developmental dyslexia (DD) is a neurodevelopmental condition with complex genetic mechanisms. A number of candidate genes have been identified, some of which are linked to neuronal development and migration and to ciliary functions. However, expression and regulation of these genes in human brain development and neuronal differentiation remain uncharted. Here, we used human long-term self-renewing neuroepithelial stem (lt-NES, here termed NES) cells derived from human induced pluri- potent stem cells to study neuronal differentiation in vitro. We characterized gene expression changes during differentiation by using RNA sequencing and validated dynamics for selected genes by qRT-PCR. Interestingly, we found that genes related to cilia were significantly enriched among upregulated genes during differentiation, including genes linked to ciliopathies with neurodevelopmental phenotypes. We confirmed the presence of primary cilia throughout neuronal differentiation. Focusing on dyslexia candidate genes, 33 out of 50 DD candidate genes were detected in NES cells by RNA sequencing, and seven candidate genes were upregulated during differentiation to neurons, including DYX1C1 (DNAAF4), a highly replicated DD candidate gene. Our results suggest a role of ciliary genes in differentiating neuronal cells and show that NES cells provide a relevant human neuronal model to study ciliary and DD candidate genes. Keywords Cilia . Ciliopathies . Reading disorder . Human neuroepithelial stem cells . RNA sequencing Abbreviations DD Developmental dyslexia BBS Bardet-Biedl syndrome DNAAF Dynein axonemal assembly factor CAGE Cap analysis of gene expression DYX1C1 Dyslexia susceptibility 1 candidate 1 DAVID Database for Annotation, EGF Epidermal growth factor Visualization and Integrated Discovery FANTOM Functional annotation of the DCDC2 Doublecortin domain containing 2 mammalian genome DCG Dyslexia candidate gene FDR False discovery rate DCX Doublecortin FGF Fibroblast growth factor Andrea Bieder and Masahito Yoshihara contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-01905-6) contains supplementary material, which is available to authorized users. * Andrea Bieder 3 Research Program of Molecular Neurology, Research Programs [email protected] Unit, University of Helsinki, Helsinki, Finland * Juha Kere 4 Folkhälsan Institute of Genetics, Helsinki, Finland [email protected] 5 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden 1 Department of Biosciences and Nutrition, Karolinska Institutet, 6 School of Basic and Medical Biosciences, King’s College London, Hälsovägen 9, 141 57 Huddinge, Sweden London, UK 2 Competence Centre on Health Technologies, Tartu, Estonia 7 Department of Medicine, Solna, Karolinska Institutet, Solna, Sweden Mol Neurobiol (2020) 57:2944–2958 2945 GEO Gene Expression Omnibus phenotype of DD, it is important to address DCG regulation in GO Gene ontology a human neuronal system. However, a systematic assessment GPCR G protein coupled receptor of DCGs in human neuronal development is so far lacking. To GSEA Gene set enrichment analysis study human-specific gene regulatory events and hESC Human embryonic stem cell neurodevelopmental disorders, modeling human brain devel- hiPSC Human induced pluripotent stem cell opment in vitro derived from induced pluripotent stem cells IFT57 Intraflagellar transport 57 (iPSCs)/embryonic stem cells (ESCs) combined with JBTS Joubert syndrome transcriptomic characterization has become a crucial tool MAP2 Microtubule-associated protein 2 [20]. Human long-term self-renewing neuroepithelial stem MKS Meckel-Gruber syndrome (lt-NES, here termed NES) cells derived from human iPSCs NES cells Long-term self-renewing (hiPSCs) can mimic human neuronal development in vitro. neuroepithelial stem cells They resemble neuroepithelial cells in vivo, self-renew in NPC Neural progenitor cell the presence of fibroblast growth factor (FGF) and epidermal OFD Orofaciodigital syndrome growth factor (EGF), and can differentiate into neuronal and PCA Principal component analysis glial cells [21–23]. They have been used as a model for PCNT Pericentrin neurodevelopmental processes and disorders [24, 25]. STRT Single cell tagged reverse transcription Here, we sought to map gene expression changes during TCTN2 Tectonic family member 2 early human neuronal development in vitro with a focus on TMEM231 Transmembrane protein 231 DCG regulation. We monitored gene expression throughout TUBA1A Tubulin α1α differentiation from NES cells to neuronal cells by RNA- TUBB3 Tubulin β3 sequencing (RNA-seq) on bulk RNA samples. In addition, UMI Unique molecular identifier we characterized specifically the dynamics of DCG expression. Introduction Materials and Methods Developmental dyslexia (DD) is a learning disorder with a neurodevelopmental origin. It is the most common learning Cell Culture disorder present in about 5–10% of the population. Early stud- ies in postmortem human brains have suggested underlying The ethical guidelines for derivation of cell line AF22 neuronal migration anomalies [1]. DD is highly heritable and were described previously [21]. Reprogramming of hu- many candidate genes have been proposed [2](Suppl. man cells was permitted by Regional ethical committee Table 1). Some of the most genetically replicated DD candi- Stockholm (Dnr 2012/208–31/3). The derivation and cul- date genes (DCGs), namely DYX1C1, DCDC2,and turing of NES cells (line AF22, derived from a healthy KIAA0319, have been implied in neuronal development and female person) were described previously [21, 25]. migration in rodents, supporting the early studies in human Briefly, NES cells were cultured in DMEM/F12+ brains [3–5]. Interestingly, the same genes have been shown Glutamax supplemented with penicillin (100 U/ml), strep- independently to have a role in ciliary biology [6–11]. Cilia tomycin (100 μg/ml), N2 (1:100), B27 (1:1000), FGF are present on mammalian neuronal cells at different stages of (10 ng/ml) (all from Life Technologies, Thermo Fisher development—in progenitor cells and post-mitotic neurons Scientific, Carlsbad, CA, USA), and EGF (10 ng/ml; [12]. At present, little is known about their function in neuro- Peprotech, Rocky Hill, NJ, USA) in a 5% CO2 incubator. nal development and homeostasis, and their roles in neuronal Half of the medium was changed daily, and cells were proliferation, migration, and maturation are just beginning to passaged at a ratio of 1:3 upon confluency. Plates were be elucidated [13]. Many ciliopathies show neurologic symp- pre-coated using poly-ornithine (0.1 mg/ml; Sigma- toms, and cilia have been linked to neuropsychiatric disorders Aldrich, St. Louis, MO, USA) and laminin (2 μg/ml; [14–18]. Sigma-Aldrich, L2020). For differentiation, cells were In contrast to the vast literature on genetic studies of DCGs, plated in complete medium for 2 days, then medium was few functional studies have been carried out. Some studies in changed to medium without growth factors FGF and EGF. animal model systems and cell lines have addressed the regu- After 1 week, medium was changed to a 1:1 mixture of lation and functions of DYX1C1, DCDC2, and KIAA0319 DMEM/F12+Glutamax and Neurobasal (Life (reviewed in [19]). However, their function in human neuro- Technologies) containing N2 (1:200)
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