The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth

Abstract

Loss-of-function mutations in UPF3B result in variable clinical presentations including intellectual disability (ID, syndromic and non-syndromic), autism, childhood onset schizophrenia and attention deficit hyperactivity disorder. UPF3B is a core member of the nonsense-mediated mRNA decay (NMD) pathway that functions to rapidly degrade transcripts with premature termination codons (PTCs). Traditionally identified in thousands of human diseases, PTCs were recently also found to be part of 'normal' genetic variation in human populations. Furthermore, many human transcripts have naturally occurring regulatory features compatible with 'endogenous' PTCs strongly suggesting roles of NMD beyond PTC mRNA control. In this study, we investigated the role of Upf3b and NMD in neural cells. We provide evidence that suggests Upf3b-dependent NMD (Upf3b-NMD) is regulated at multiple levels during development including regulation of expression and sub-cellular localization of Upf3b. Furthermore, complementary expression of Upf3b, Upf3a and Stau1 stratify the developing dorsal telencephalon, suggesting that alternative NMD, and the related Staufen1-mediated mRNA decay (SMD) pathways are differentially employed. A loss of Upf3b-NMD in neural progenitor cells (NPCs) resulted in the expansion of cell numbers at the expense of their differentiation. In primary hippocampal neurons, loss of Upf3b-NMD resulted in subtle neurite growth effects. Our data suggest that the cellular consequences of loss of Upf3b-NMD can be explained in-part by changes in expression of key NMD-feature containing transcripts, which are commonly deregulated also in patients with UPF3B mutations. Our research identifies novel pathological mechanisms of UPF3B mutations and at least partly explains the clinical phenotype of UPF3B patients.

Nonsense-mediated mRNA decay in humans at a glance

“…In humans, two UPF3 paralogs, UPF3 and UPF3X (also called UPF3A and UPF3B, respectively), differently modulate NMD activity (Chan et al, 2009;Kunz et al, 2006;Lykke-Andersen et al, 2000;Serin et al, 2001) in ways that, like UPF1 and another NMD factor, UPF2, have been shown to be crucial for, for example, normal neuronal maturation and development (Colak et al, 2013;Jolly et al, 2013;Laumonnier et al, 2010;Lou et al, 2014;Nguyen et al, 2012Nguyen et al, , 2013Tarpey et al, 2007). UPF3 or UPF3X are generally associated with exon junction complexes (EJCs; see below) that are deposited in the nucleus upstream of newly spliced exon-exon junctions, whereas UPF2 is generally associated with EJCs after newly synthesized mRNAs are exported to the cytoplasm (Kim et al, 2001;Lejeune et al, 2002;Lykke-Andersen et al, 2001).…”

Modeling Fragile X syndrome in neurogenesis: An unexpected phenotype and a novel tool for future therapies

“…[25][26][27] Indeed, premature neurogenesis has been associated to gross brain abnormalities in a thalassemia/mental retardation syndrome X-linked (ATRX), consistently with the microcephaly observed in patients affected by this disorder. 28,29 Similarly, accelerated cell cycle and overproduction of GABAergic inhibitory neurons were described in iPSC-derived brain organoids of Autism Spectrum Disorder (ASD) patients characterized by macrocephalia.…”

RNA decay, evolution, and the testis

“…42,49,50 While the underlying basis for its role in neural development and cognition are not known, in vitro studies have shown that UPF3B promotes neural differentiation and it is regulated by neurally expressed microRNAs that influence neural self-renewal vs. differentiation decisions. 20,29 UPF3B also shapes the unfolded protein response, a pathway critical for normal neural development. 21 Until recently, the functional role of UPF3B's paralog partner-UPF3A-has been unclear.…”

“…8,35,50 UPF3B promotes the differentiation of neural progenitor cells and may be involved in the ability of NMD to influence neural proliferation versus differentiation decisions by virtue of its ability to degrade specific transcripts. 20,29 Thus, by subtly controlling the stabilities of batteries of mRNAs, the UPF3B branch of NMD may have played an important role in the evolution of the vertebrate brain.…”