Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.
Highlights
Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders, leading to the progressive degeneration of the α-motor neurons in the spinal cord [1]
With the purpose of characterizing spinal cord-derived neural stem cells (NSCs), we isolated these neural precursors from E13.5 SMNΔ7 SMA and wild type (WT) mice, and obtained long-lasting cultures of cells growing as neurospheres
RT-PCR analysis was performed, revealing that NSCs derived from spinal cord expressed the anterior transcription factors Hoxb4 and Hoxb9 [26] (Figure 1B), while neurospheres derived from the brain of a WT littermate did not
Summary
Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders (incidence of 1–5000 to 1–10,000), leading to the progressive degeneration of the α-motor neurons in the spinal cord [1]. The disease is caused by the deletion or mutations of survival motor neuron-1 gene (SMN1), resulting in very low levels of functional SMN protein [2]. As there are no effective treatments for this devastating disorder, studying the unique biology of these important cells has been the focus of intense research and, at the organismal level, animal models of SMA are of invaluable importance to address the above points For this reason, several different mouse models have been generated with varying degrees of phenotypic severity [12]. Few studies have started addressing the role of miRNAs in NSCs, in the developing spinal cord [21,22,23,24] where the lower (α) motor neurons affected by SMA reside. We profile the microRNA expression differences distinguishing SMA from WT NSCs, and speculate a possible correlation between some of these microRNAs and the difference in proliferation shown by SMA spinal cord-derived NSCs compared to the wild type
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