A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

Abstract

Spinal muscular atrophy (SMA) is the most common genetic disease in children. SMA is generally caused by mutations in the gene SMN1. The survival of motor neurons (SMN) complex consists of SMN1, Gemins (2-8), and Strap/Unrip. We previously demonstrated smn1 and gemin5 inhibited tissue regeneration in zebrafish. Here we investigated each individual SMN complex member and identified gemin3 as another regeneration-essential gene. These three genes are likely pan-regenerative, since they affect the regeneration of hair cells, liver, and caudal fin. RNA-Seq analysis reveals that smn1, gemin3, and gemin5 are linked to a common set of genetic pathways, including the tp53 and ErbB pathways. Additional studies indicated all three genes facilitate regeneration by inhibiting the ErbB pathway, thereby allowing cell proliferation in the injured neuromasts. This study provides a new understanding of the SMN complex and a potential etiology for SMA and potentially other rare unidentified genetic diseases with similar symptoms.npj Regenerative Medicine (2020) 5:6 ; https://doi.

The RBS1 domain of Gemin5 is intrinsically unstructured and interacts with RNA through conserved Arg and aromatic residues

“…The protein was initially reported as the RNA-binding protein (RBP) of the survival of motor neurons (SMN) complex [ 2 ]. More recently, the protein has been implicated in translation control, and gene expression reprogramming [ 3 , 4 , 5 ].…”

Emerging Roles of Gemin5: From snRNPs Assembly to Translation Control

“…Among others, Gemin5 has been identified as a signal recognition particle (SRP)-interacting protein [63], as a ribosome-interacting factor [64,65], as a translation regulator of several mRNAs [66][67][68][69], or as a factor involved in trans-splicing [70]. Further supporting the involvement of this multifaceted protein in different activities, recent data have shown that Gemin5 can act as a reprogramming factor in zebrafish lateral line hair cells, allowing for a shift toward cell survival [71]. In addition, an RNA-Seq analysis revealed that the gemin5, together with smn1 and gemin3 genes, are linked to a common set of genetic pathways, including the tumor protein tp53 and the epidermal growth factor receptor ErbB pathways.…”

“…In recent years, Gemin5 has emerged as a critical factor during translational reprogramming events, although the mechanisms underlying this phenomenon are still poorly known [71]. In this respect, previous studies have shown that Gemin5 regulates translation through its capacity to recognize a selective subset of mRNAs [68] and also serves as a hub for numerous RBPs [64] that, in turn, are involved in gene expression control.…”

Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

“…Accordingly, Gemin5 acts as a hub for several networks performing diverse key cellular functions. This multifunctional protein has been shown to act as a regulator of translation ( Pacheco et al, 2009 ; Workman et al, 2015 ; Francisco-Velilla et al, 2018 ), as a ribosome-interacting protein ( Francisco-Velilla et al, 2016 ; Simsek et al, 2017 ), as a reprogramming factor in zebrafish lateral line hair cells ( Pei et al, 2020 ), as a signal recognition particle-interacting protein ( Piazzon et al, 2013 ), and as a trans-splicing factor ( Philippe et al, 2017 ). In addition, Gemin5 has been identified as a member of RNP networks associated to distinct cytoplasmic aggregates ( Jiang et al, 2018 ; Vu et al, 2021 ; Wollen et al, 2021 ).…”