From wings to whiskers to stem cells: why every model matters in fragile X syndrome research

Abstract

Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads to the loss of its protein product, fragile X messenger ribonucleoprotein (FMRP). It is the most prevalent inherited form of intellectual disability and the highest single genetic cause of autism. Since the discovery of the genetic basis of FXS, extensive studies using animal models and human pluripotent stem cells have unveiled the functions of FMRP and mechanisms underlying FXS. However, clinical trials have not yielded successful treatment. Here we review what we have learned from commonly used models for FXS, potential limitations of these models, and recommendations for future steps.

Keywords: Drosophila; FMR1; FMRP; Fragile X syndrome; Human; Mouse; Neuron; Organoid; Stem cells; iPSCs.

Fig. 1

Comparison of phenotypes of FXS patients to those observed in in vitro. FXS human stem cell models and mouse FXS models. The symptoms in FXS patients (top hexagon) range from mild to severe. Some characteristics of FXS in patients overlap with autistic features such as intellectual disability, increased anxiety, decreased social interaction, and seizures during a young age. In pursuit of understanding the biological pathways behind FXS symptomology, some of these phenotypes have been successfully replicated in human pluripotent stem cells (hPSC) in vitro (bottom left hexagon) and mouse models of FXS (bottom right hexagon). The shared phenotypes include increased protein synthesis, abnormal neuronal activity, and increased synapse density. There are also some features that are unique to each model. In hPSC in vitro models, a prominent phenotype includes hyperexcitability and disruptions in NPC proliferation in cortical neurons and organoids. While in mouse models audiogenic seizures, immature spines, and disorganization in cortical layer formation have been observed. A main advantage to using hPSC in vitro models is that these neurons can be derived from FXS patient iPSCs that contain the epigenetic silencing of FMR1 not found in mouse models allowing for more comprehensive biochemical analyses. However, in mouse models, behavior that can be correlated to FXS patients can be studied as has been done when assessing hyperactivity, compulsive behaviors, learning and memory deficits, as well as EEG properties. Overall, complementary model systems are needed to fully understand FXS. Please see Table S1 for a complete list and references. Figure created in BioRender.com.