Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome

Abstract

Lack of FMR1 protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms resulting in neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic brake of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. There was evidence of human iPSC line donor-dependent variation reflecting potentially phenotypic variation. NPCs derived from an FXS male with concomitant epilepsy expressed differently several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in NPCs modeling FXS with epilepsy. Our results demonstrated potential of human iPSCs in disease modeling for discovery and development of therapeutic interventions by showing early gene expression changes in FXS iPSC-derived NPCs consistent with the known pathophysiological changes in FXS and by revealing disturbed FXS progenitor growth linked to reduced expression of LYNX1, suggesting dysregulated cholinergic system.

Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders

“…Therefore, it's conceivable that β2-subunits may be preferentially translated when eIF4E is overexpressed, resulting in nAChR with altered subunit compositions and impaired desensitization dynamics. In line with this speculation, recent findings have demonstrated a selectively high expression of CHRNB2, which encodes the β2 subunits of nAChR, in patient-derived induced pluripotent stem cells (iPSCs) from individuals with FXS 99 .…”

“…The copyright holder for this preprint this version posted January 30, 2024. ; https://doi.org/10.1101/2024.01.29.577831 doi: bioRxiv preprint with altered subunit compositions and impaired desensitization dynamics. In line with this speculation, recent findings have demonstrated a selectively high expression of CHRNB2, which encodes the β2 subunits of nAChR, in patient-derived induced pluripotent stem cells (iPSCs) from individuals with FXS 99 .…”

Astrocytes in fragile X syndrome

“…Mitochondrial respiration capacity and emission of reactive oxygen species are increased in Fmr1 KO mouse astrocytes under physiological hypoxia but not in atmospheric normoxia ( Vandenberg et al, 2022 ). In the transcriptomics analysis of human FXS NPCs, MYD88 was amongst the most significantly overexpressed genes ( Talvio et al, 2022 ) and there are several tentative arguments for MYD88-mediated system overactivity in FXS astrocytes. Expression of MMP-9, the proposed target of minocycline in FXS, is upregulated via a MYD88-dependent mechanism in astrocytes ( Gorina et al, 2011 ), and reduced IL-10 in FXS astrocytes ( Talvio et al, 2023 ) might contribute to increased MYD88 ( Chang et al, 2009 ).…”

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

“…However, emerging research suggests that astrocytes, an abundant glial cell type in the CNS, also play a role. [6][7][8] During development, astrocytes secrete temporally regulated signals to promote dendrite growth and synapse formation, maturation, and function. 9 Astrocyte-specific Fmr1 KO and re-expression studies highlight a role for astrocytes in some Fmr1 KO cortical excitability and behavioral phenotypes.…”