Abstract
SOX10 is a Sry-related high mobility (HMG)-box transcriptional regulator that promotes differentiation of neural crest precursors into Schwann cells, oligodendrocytes, and melanocytes. Myelin, formed by Schwann cells in the peripheral nervous system, is essential for propagation of nerve impulses. SWI/SNF complexes are ATP dependent chromatin remodeling enzymes that are critical for cellular differentiation. It was recently demonstrated that the BRG1 subunit of SWI/SNF complexes activates SOX10 expression and also interacts with SOX10 to activate expression of OCT6 and KROX20, two transcriptional regulators of Schwann cell differentiation. To determine the requirement for SWI/SNF enzymes in the regulation of genes that encode components of myelin, which are downstream of these transcriptional regulators, we introduced SOX10 into fibroblasts that inducibly express dominant negative versions of the SWI/SNF ATPases, BRM or BRG1. Dominant negative BRM and BRG1 have mutations in the ATP binding site and inhibit gene activation events that require SWI/SNF function. Ectopic expression of SOX10 in cells derived from NIH 3T3 fibroblasts led to the activation of the endogenous Schwann cell specific gene, myelin protein zero (MPZ) and the gene that encodes myelin basic protein (MBP). Thus, SOX10 reprogrammed these cells into myelin gene expressing cells. Ectopic expression of KROX20 was not sufficient for activation of these myelin genes. However, KROX20 together with SOX10 synergistically activated MPZ and MBP expression. Dominant negative BRM and BRG1 abrogated SOX10 mediated activation of MPZ and MBP and synergistic activation of these genes by SOX10 and KROX20. SOX10 was required to recruit BRG1 to the MPZ locus. Similarly, in immortalized Schwann cells, BRG1 recruitment to SOX10 binding sites at the MPZ locus was dependent on SOX10 and expression of dominant negative BRG1 inhibited expression of MPZ and MBP in these cells. Thus, SWI/SNF enzymes cooperate with SOX10 to directly activate genes that encode components of peripheral myelin.
Highlights
Glial cells insulate axons by forming a lipid rich structure called the myelin sheath [1]
We found that SOX10 can activate expression of two myelin genes, myelin protein zero (MPZ) and myelin basic protein (MBP) in these cells and that induction of dominant negative BRM or BRG1 inhibits expression of both myelin genes
In order to determine whether SOX10 can convert these cells into myelin gene expressing cells and to test the requirement for SWI/SNF enzymes in the activation of these genes, we introduced SOX10 by retroviral infection into a dominant negative BRM cell line (H17), and a dominant negative BRG1 cell line (B22) that had been grown in the presence or absence of tetracycline and cultured in low serum media to promote differentiation
Summary
Glial cells insulate axons by forming a lipid rich structure called the myelin sheath [1]. Inherited neuropathies of the PNS are characterized by mutations in genes that encode essential components of myelin and transcriptional regulators of Schwann cell development. SOX10 is a Sry-related high mobility (HMG)-box transcriptional regulator that promotes differentiation of neural crest precursors into the glial lineage and is involved in melanocyte differentiation [4]. During early stages of differentiation, SOX10 promotes expression of low levels of myelin protein zero (MPZ), a major component of myelin that is expressed in Schwann cells [5]. In the step, promyelinating Schwann cells transition to myelinating cells as SOX10 and KROX20 synergistically activate high levels of MPZ and the expression of genes encoding other components of myelin [8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
