PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

Abstract

Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders.

Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5–15kD

“…In their study, knockdown of PQBP1 profoundly impaired the formation of the primary cilium in hippocampal neurons and the mouse cerebral cortex in vivo 31 . These results suggest that the loss of function of PQBP1 is responsible for the biological dysfunctions underlying mental retardation disorders 12,[19][20][21][22] .…”

“…PQBP1 is dominantly expressed in the central nervous system in embryos and in newborn mice 20 , and PQBP1 knockdown results in impairment of anxiety-related cognition and memory 19 . A recent study by Wang et al 22 has shown that PQBP1 knockdown in primary mouse neurons results in aberrant alternative splicing of pre-mRNAs that are important for neuron projection development, although the precise mechanism by which this occurs remains to be explored. In addition, Ikeuchi et al 31 have identified a function for PQBP1 in the morphogenesis of the primary cilium in postmitotic neurons.…”

The PSI–U1 snRNP interaction regulates male mating behavior in Drosophila

“…3A). To detect, compare, and quantitate differences in pre-mRNA splicing patterns between the full-length PSI and the PSIΔAB mutant, we used three different computational methods [MISO (12), JuncBase (13), and the Junction Use Model (JUM) (14)] (Fig. 3B, Fig.…”

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

“…Most human disease-causing PQBP1 mutations truncate the C-terminal domain of PQBP1 that is required for interaction with the spliceosomal protein U5-15kD (Waragai et al, 2000;Zhang et al, 2000). Knockdown of PQBP1 in mouse embryo primary neurons reduces general splicing efficiency and promotes the use of alternative splice sites in a variety of transcripts (Wang et al, 2013). A missense mutation within the WW domain at the N-terminus of PQBP1 in Golabi-Ito-Hall (GIH) patients (Y65C) causes abnormal pre-mRNA splicing and inhibits PQBP1 binding to spliceosome components and a partner protein, WBP11 (Lubs et al, 2006;Tapia et al, 2010;Sudol et al, 2012).…”

“…PQBP1 interacts with the C-terminus of activated RNA polymerase II (Okazawa et al, 2002) and with spliceosome components, including U5-15kD (Dim1p) (Waragai et al, 2000;Zhang et al, 2000) and the U2 snRNP component Sf3b1 (Wang et al, 2013). Most human disease-causing PQBP1 mutations truncate the C-terminal domain of PQBP1 that is required for interaction with the spliceosomal protein U5-15kD (Waragai et al, 2000;Zhang et al, 2000).…”