Concise Review: Fragile X Proteins in Stem Cell Maintenance and Differentiation

Abstract

Fragile X syndrome (FXS), the most common genetic form of autism spectrum disorder, is caused by deficiency of the fragile X mental retardation protein (FMRP). Despite extensive research and scientific progress, understanding how FMRP regulates brain development and function remains a major challenge. FMRP is a neuronal RNA-binding protein that binds about a third of messenger RNAs in the brain and controls their translation, stability, and cellular localization. The absence of FMRP results in increased protein synthesis, leading to enhanced signaling in a number of intracellular pathways, including the mTOR, mGLuR5, ERK, Gsk3β, PI3K, and insulin pathways. Until recently, FXS was largely considered a deficit of mature neurons; however, a number of new studies have shown that FMRP may also play important roles in stem cells, among them neural stem cells, germ line stem cells, and pluripotent stem cells. In this review, we will cover these newly discovered functions of FMRP, as well as the other two fragile X-related proteins, in stem cells. We will also discuss the literature on the use of stem cells, particularly neural stem cells and induced pluripotent stem cells, as model systems for studying the functions of FMRP in neuronal development.

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

“…In healthy individuals, FMRP is upregulated during development of the neural lineage [52,53], suggesting that it is involved in progression of neural development, and that at different stages of neurodevelopment, FMRP regulates different targets. Indeed, several developmental functions have been found for FMRP linked to maintenance and differentiation of embryonic and adult stem cells [4]. In this study, we have shown that a partial reduction in FMRP expression was Values were normalized to GAPDH.…”

“…FMR1 is inactivated because of a dynamic mutation composed of a CGG-triplet repeat expansion in the 5¢-untranslated region of the gene [2]. In human fetuses affected by the full mutation, FMR1 is gradually downregulated during embryonic development [3] and its consequent adverse effects on brain function suggest a role for FMRP in early neurogenesis, including maintenance and differentiation of neural progenitor cells [4].…”

Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms

“…and all three RNA-binding proteins are enriched in neurons. They share similar functional domains, but diverge in the C-termini and in the nucleolar localization signal sequence, suggesting they possess both common and distinct functions (Darnell et al, 2009; Li and Zhao, 2014). Studies have shown that FXS proteins have the ability to interact with each other, and FMRP and FXR2P double knockout mice display more severe neurobehavioral abnormalities compared to single-mutant mice (Spencer et al, 2006).…”

Human iPSC Models: A Platform for Investigating Neurodevelopmental Diseases

“…Several groups have generated disease-specific lines from patients with monogenic autism spectrum disorders including Rhett [87], Fragile X [88] and Timothy Syndromes [89]. The objectives of these studies are to identify functional disease-specific phenotypes and to examine whether these phenotypes can be rescued by therapeutic interventions.…”

“…FMRP functions as an RNA binding protein where it regulates aspects of translation, stability and cell localization. A lack of FMRP enhances intracellular signaling in the mTOR, GluR5, ERK, GSK3β, insulin and PI3K pathways [88]. Neural stem cell plasticity and this cell's ability to change phenotype responding to signals from the environment may be impacted by the FMRP protein [96].…”