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

Andrea Bieder,Masahito Yoshihara,Juha Kere,Kaarel Krjutškov,Anna Falk,Shintaro Katayama,Isabel Tapia-Páez

doi:10.1007/s12035-020-01905-6

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 pluripotent 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.

Highlights

Developmental dyslexia (DD) is a learning disorder with a neurodevelopmental origin
To make sure that the enrichment of ciliary genes is not a false positive signal due to a high number of tubulin genes upregulated in neurons, we examined the genes enriched in the cilium morphogenesis and cilium assembly categories
We focused on a set of DD candidate genes (DCGs) that has been highly replicated in genomic studies, namely DYX1C1, DCDC2, and KIAA0319 [43]

Summary

Introduction

Developmental dyslexia (DD) is a learning disorder with a neurodevelopmental origin. It is the most common learning disorder present in about 5–10% of the population. Studies in postmortem human brains have suggested underlying neuronal migration anomalies [1]. Some of the most genetically replicated DD candidate genes (DCGs), namely DYX1C1, DCDC2, and KIAA0319, have been implied in neuronal development and migration in rodents, supporting the early studies in human brains [3,4,5]. Little is known about their function in neuronal development and homeostasis, and their roles in neuronal proliferation, migration, and maturation are just beginning to be elucidated [13]. Many ciliopathies show neurologic symptoms, and cilia have been linked to neuropsychiatric disorders [14,15,16,17,18]

Methods

Results

Conclusion