Sox10 Is an Active Nucleocytoplasmic Shuttle Protein, and Shuttling Is Crucial for Sox10-Mediated Transactivation

Abstract

Sox10 belongs to a family of transcription regulators characterized by a DNA-binding domain known as the HMG box. It plays fundamental roles in neural crest development, peripheral gliogenesis, and terminal differentiation of oligodendrocytes. In accord with its function as transcription factor, Sox10 contains two nuclear localization signals and is most frequently detected in the nucleus. In this study, we report that Sox10 is an active nucleocytoplasmic shuttle protein, competent of both entering and exiting the nucleus. We identified a functional Rev-type nuclear export signal within the DNA-binding domain of Sox10. Mutational inactivation of this nuclear export signal or treatment of cells with the CRM1-specific export inhibitor leptomycin B inhibited nuclear export and consequently nucleocytoplasmic shuttling of Sox10. Importantly, the inhibition of the nuclear export of Sox10 led to decreased transactivation of transfected reporters and endogenous target genes, arguing that continuous nucleocytoplasmic shuttling is essential for the function of Sox10. To our knowledge this is the first time that nuclear export has been reported and shown to be functionally relevant for any Sox protein.

Expression of LHX3 and SOX2 during mouse inner ear development

“…In contrast, SOX2 immunoreactivity is gradually lost from the nuclei of both inner and outer hair cells, although some expression does persist transiently in the hair cell cytoplasm ( Figure 3E). The sub-cellular distribution of other SOX family members (e.g., Group E) is important for regulation of their activity (Rehberg et al, 2002), and this property has also been described for SOX2 (Avilion et al, 2003;Rehberg et al, 2002). At this stage of inner ear development, cells in the SOX2-expressing region of the GER are undergoing cellular rearrangements that eventually give rise to the inner sulcus.…”

Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors

“…The SoxE HMG box domain also features a nuclear export signal (Gasca et al, 2002;Rehberg et al, 2002). Whether nuclear import and export constitute a general mechanism to regulate Sox protein activity in vivo is a question that has only been addressed for a few Sox proteins so far.…”

Regulation of Merkel cell development by Pax6

“…Sox10, which regulates many aspects of embryonic development, and Vax2, which participates with Pax6 in retinal development, both dynamically shuttle between the nucleus and the cytoplasm with consequences for their transcriptional activity (Rehberg et al, 2002;Kim and Lemke, 2006). Pax6 interacts with some secreted cytoplasmic proteins such as SPARC (secreted protein acidic and rich in cysteine), a matricellular protein that regulates transport and processing of Pax6 during neuronal primary culture, in the cerebellum and cortex of the mouse brain (Tripathi and Mishra, 2010).…”