Positive feedback loop between Sox2 and Sox6 inhibits neuronal differentiation in the developing central nervous system

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (7), p.2794-2799
• Main Authors: Lee, Kyung Eun, Seo, Jihae, Shin, Jiheon, Ji, Eun Hye, Roh, Jiwon, Kim, Joo Yeon, Sun, Woong, Muhr, Jonas, Lee, Sanghyuk, Kim, Jaesang
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological Sciences; Cell Differentiation - physiology; Cells; Central nervous system; Central Nervous System - embryology; Chick Embryo; Chromatin Immunoprecipitation; DNA Primers - genetics; Embryos; Feedback, Physiological - physiology; Gene expression; Genes; Immunohistochemistry; In Situ Hybridization; Medicin och hälsovetenskap; Molecular Sequence Data; Multipotent stem cells; Nervous system; Neural stem cells; Neurogenesis - physiology; Neurons; Neurons - physiology; Progenitor cells; RNA; Sequence Analysis, DNA; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; SOXD Transcription Factors - genetics; SOXD Transcription Factors - metabolism; Stem cells; Transcription factors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1308758111

How a pool of undifferentiated neural progenitor cells is maintained in the developing nervous system is an issue that remains unresolved. One of the key transcription factors for self-renewal of these cells is Sox2, the forced expression of which has been shown to inhibit neuronal differentiation in vivo. To dissect the molecular mechanisms of Sox2 activity, a ChIP-on-chip assay has been carried out for Sox2, and multiple candidate direct target genes have been isolated. In this report, we provide evidence indicating that Sox6 , which like Sox2 belongs to the SRY-related HMG box transcription factor family, is a bona-fide direct regulatory target of Sox2. In vivo, Sox6 expression is seen with a temporal lag in Sox2-positive neural precursor cells in the ventricular zone, and Sox2 promotes expression of Sox6 as a transcriptional activator. Interestingly, gain- and loss-of-function assays indicate that Sox6 in turn is required for the maintenance of Sox2 expression, suggesting that a positive feedback loop, which functions to inhibit premature neuronal differentiation, exists between the two transcription factors.