hnRNP A1B, a Splice Variant of HNRNPA1, Is Spatially and Temporally Regulated

Abstract

RNA binding proteins (RBPs) play a key role in cellular growth, homoeostasis and survival and are tightly regulated. A deep understanding of their spatiotemporal regulation is needed to understand their contribution to physiology and pathology. Here, we have characterized the spatiotemporal expression pattern of hnRNP A1 and its splice variant hnRNP A1B in mice. We have found that hnRNP A1B expression is more restricted to the CNS compared to hnRNP A1, and that it can form an SDS-resistant dimer in the CNS. Also, hnRNP A1B expression becomes progressively restricted to motor neurons in the ventral horn of the spinal cord, compared to hnRNP A1 which is more broadly expressed. We also demonstrate that hnRNP A1B is present in neuronal processes, while hnRNP A1 is absent. This finding supports a hypothesis that hnRNP A1B may have a cytosolic function in neurons that is not shared with hnRNP A1. Our results demonstrate that both isoforms are differentially expressed across tissues and have distinct localization profiles, suggesting that the two isoforms may have specific subcellular functions that can uniquely contribute to disease progression.

Type I PRMT inhibitor MS023 promotesSMN2exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

“…No further amelioration was observed with 40 mg/kg MS023, hinting that with this dose the therapeutic window has been surpassed (Figure 3B, Supplementary Figure 3A). Notably, we only detected an increase in FL SMN2 transcript and SMN protein levels in spinal cords and skeletal muscles of SMA mice treated with 2 mg/kg MS023, where hnRNPA1 is most abundantly expressed (81),(82) (Figure 3D–G; Supplementary Figure 3B and C).…”

hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target

“…Secondly, hnRNP A1 cooperates with other hnRNPs family members to modulate gene alternative splicing. hnRNP A1B-hnRNP A1 heterodimer was observed in neurons (Gagne et al, 2021). The heterotypic interactions between hnRNP H and hnRNP A1 in live cells can be captured in live cells through BRET signals mediated by the C-terminal of hnRNP A1 and H (Fisette et al, 2010).…”

“…Firstly, the homotypic interactions of hnRNP A1 via its UP1 domain have been documented using the bioluminescence resonance energy transfer (BRET) technology (Ding et al, 1999;Fisette et al, 2010). Like hnRNP A1, the longer isoform hnRNP A1B also exhibits homotypic interactions (Gueroussov et al, 2017;Gagne et al, 2021). Other RBPs, such as hnRNP C and TDP-43, have been shown to dimerize, suggesting that dimerization could affect their functions (Shiina et al, 2010;Cienikova et al, 2015).…”

hnRNPs: roles in neurodevelopment and implication for brain disorders

“…The spatiotemporal regulation of hnRNPs is illustrated by: (i) PTBP1 (hnRNP I) and PTBP2 (nPTB), whose expressions are almost mutually exclusive. During brain development, cells switch from expressing hnRNP I (PTBP1) to PTBP2, thereby contributing to the neuronal differentiation process ( Boutz et al, 2007 ), and (ii) hnRNP A1 and one of its isoforms, hnRNP A1B show different expression pattern and subcellular localization with hnRNP A1B more restricted to the central nervous system and found in neuronal processes compared to hnRNP A1 ( Gagné et al, 2021 ).…”