Biochemical and Biophysical Research Communications
Sox11 promotes endogenous neurogenesis and locomotor recovery in mice spinal cord injury
Introduction
In mammals, the central nervous system (CNS) is sensitive to mechanical injuries that cause permanent functional deficits. Mechanical forces imparted to the spinal cord can produce an immediate disruption of the tissue, with direct axonal and neuronal injury leading to neuronal death. Neuronal death may occur until hours or days after spinal cord injury (SCI) as a result of ensuing secondary pathological processes. Although a number of strategies have been applied to protect injured spinal cords from secondary pathological processes and promote neuronal survival and synaptic plasticity, no fully restorative therapies currently exist for mammalian SCI [1], [2]. Over the past few decades, the discovery of endogenous multipotent stem cell populations in specialized niches of the adult CNS has fueled interest in regenerative therapies based on the recruitment of endogenous stem or progenitor cells [3], [4]. Investigations with neural stem cells (NSCs) have revealed that endogenous adult spinal cord NSCs can facilitate functional recovery but normally fail to do so efficiently. Accordingly, information regarding the modulation of endogenous NSCs to promote functional recovery would greatly enhance the potential for optimizing regenerative neurogenesis in mammals.
The Sox family of transcription factors is well-established regulators of cell fate decisions and are expressed in a tissue-specific manner during development [5], [6]. In specific, Sox11 is mainly involved in neural development and organogenesis during fetal life and functions in neural progenitor cells that have already been committed to neuronal differentiation during neural development [7], [8]. With development, Sox11 expression decreases and is absent from most normal adult tissues [9]. However, it has been reported that Sox11 expression continues in neurogenic areas of the adult brain [10]. While the exact role of Sox 11 in the adult is not known, there are data demonstrating that Sox11 is up-regulated after neural injury/disease and plays an important role in regeneration [11]. Recently, it has been shown that human glioma-initiating cells lose Sox11 expression and over-expression of Sox11 suppresses tumourigenicity by inducing neuronal differentiation [12]. Based on these findings, we hypothesized that Sox11 might have a modulating role upon endogenous NSCs during regeneration after SCI of mice.
The gene transfer for therapeutic purposes offers a valuable approach for the treatment of SCI. Recombinant lentiviral vectors have proved to be superior to other vectors with regard to gene transfer as they not only provide long-term expression of the therapeutic gene, but also serve as an efficient transducer of non-dividing cells such as neurons [13]. Therefore, in the present study, we introduced a lentiviral vector containing the Sox11 gene into injured spinal cords of mice to evaluate their therapeutic potential for the treatment of SCI.
Section snippets
Animals
Thirty-six female Kunming mice, weighing 30 ± 5 g, were obtained from the Laboratory Animal Center of Shandong University. Mice were bred and housed under standard laboratory conditions at 23 °C with an alternating 12 h light and dark cycle and free access to a commercial diet. All animal experiments were approved by the Shandong University Animal Care Committee.
Lentiviral vectors (LV) vector production
A CD511B (System Biosciences, San Francisco, USA) lentivirus vector expressing enhanced green fluorescent protein (GFP) was constructed to
The expression of Sox11 is increased in the injured spinal cord
We established mouse spinal cord hemisection model. Check whether the right hemicord was thoroughly transected under the stereo microscope (Fig. 1A). We used thirty-six mice with successful hemi-section for subsequent experiments. Expression of Sox11 in the injured spinal cord was assessed using immunohistochemical staining at 3 week after spinal cord hemisection. Sox11 expression was more robust on the injured versus contralateral side and diminished as a function of distance from the site of
Discussion
In the present study, we reported that the expression of Sox11 was increased after SCI and mainly located in ependymal cells lining the central canal and in newly-generated neurons in the spinal cord. There exists evidence from several sources indicating that the ependymal zone of the central canal may serve as a stem cell niche [18]. It had been reported that Sox11 expression is strictly confined to Doublecortin-expressing neuronally committed precursors/immature neurons in the adult brain and
Acknowledgments
This work is supported by the National Natural Science Foundation of China (Grant Nos. 81100919, 81071057, 81100849); the Scientific Research Foundation for Returned Scholars, Ministry of Education of China (21300005451001); Shangdong Province Young and Middle-Aged Scientists Research Awards Fund (BS2010YY041); Shandong postdoctoral fund (201203050).
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2017, Progress in NeurobiologyCitation Excerpt :The corticospinal tract after SCI fails to express Sox11, while its expression induced by viral vectors promotes sprouting and axon growth at both acute and chronic phase (Wang et al., 2015b). This effect can be explained by the ability of Sox11 to increase the expression of BDNF and induce the neurogenic differentiation of endogenous neural stem cells after SCI (Guo et al., 2014). Even if Sox11-miRNA connection has not been experimentally proved, it is possible to hypothesize a link between miR-145 and Sox2, another TF of the same family involved in neural differentiation after SCI.
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2016, Experimental NeurologyCitation Excerpt :Same as our previous study (Huang et al., 2015) other studies also support our observations, the astrocytes were the target cell of adeno-associated virus (AAV) vector (Petrosyan et al., 2014), lentiviral vector (Hendriks et al., 2007), and adenovirus vector (Maeda et al., 2008). However, several studies suggest that the neuron was also the target cell of other viral vectors, such as AAV (Boyce et al., 2012; Klaw et al., 2013; Van der Perren et al., 2011) and lentiviral vector (Guo et al., 2014). In the present study, we also observed exogenous PTEN being expressed at neurons (data not shown) in normal and injured spinal cords.
Ameliorative effects of baicalein in MPTP-induced mouse model of Parkinson's disease: A microarray study
2015, Pharmacology Biochemistry and BehaviorCitation Excerpt :It has been found that SOX8 knockouts have delayed oligodendrocyte terminal differentiation (Stolt et al., 2004), and SOX8 is important in initiating neural crest formation in Xenopus (O'Donnell et al., 2006). Furthermore, SOX11 is involved in adult neurogenesis at the stage of the immature neuron (Haslinger et al., 2009; Wang et al., 2013), and a recent study showed that over-expression of SOX11 promotes endogenous neurogenesis and locomotor recovery in mice spinal cord injury (Guo et al., 2014). Our results from microarray analysis and western blot showed that SOX8 and SOX11 were down-regulated at the gene and protein levels in MPTP-treated mice, while baicalein up-regulated SOX8 and SOX11 at gene and protein levels.
Methylome repatterning in a mouse model of Maternal PKU Syndrome
2014, Molecular Genetics and MetabolismCitation Excerpt :Mir463 and mir216b are down-regulated leading to increased expression of the high scoring targets Mid1 and Sox11, which are associated with Opitz Syndrome [36] and Coffin–Siris Syndrome [37] respectively. Sox11 promotes neurogenesis in a model of spinal injury [38] thus up-regulation may be defensive toward hyperphenylalaninemia-induced neural damage. Genes in Table 1 with decreased expression have potential to influence MPKU phenotypes.