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.
Highlights
Spinal muscular atrophy (SMA) is the leading hereditary cause of infant mortality[1,2]
The survival of motor neurons (SMN) complex consists of nine proteins, the majority of research on the complex has focused on the characterization of survival of motor neuron 1 (SMN1) and its role in SMA
Divergent roles for SMN complex members in embryo development and hair cell regeneration Hearing loss is one of the common sensory disorders negatively affecting the quality of life for hundreds of millions of people worldwide[15]
Summary
Spinal muscular atrophy (SMA) is the leading hereditary cause of infant mortality[1,2]. The majority of SMA cases are caused by mutations in the survival of motor neuron 1 (SMN1) gene. SMN1 is ubiquitously expressed and a reduction of SMN1 protein leads to motor neuron death in patients afflicted with SMA. Many important questions remain regarding the pathology of the disease, including why the ubiquitously expressed SMN1 protein primarily impacts motor neurons, which other organs are potentially affected by SMN1 deficiencies, and whether SMA is a developmental or degenerative disease (or both). The SMN complex consists of nine proteins, the majority of research on the complex has focused on the characterization of SMN1 and its role in SMA. A reduction of the SMN1 protein in SMA results in the reduction of other SMN complex members[13], suggesting that there is a functional inter-dependence among the nine genes
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