The Role of SOX2 in Molecular Circadian Clock Regulation and Suprachiasmatic Nucleus Development

The focal point of my doctoral research, Sox2, is a stem cell gene that has been extensively studied for its function in stem cell maintenance and proliferation, cellular reprogramming, neurogenesis, and tumorigenesis. Sox2 is expressed and maintained in stem cells of different tissues, including the developing central nervous system and adult neurogenic niches. When neural stem/progenitor cells terminally differentiate into neurons, SOX2 protein is usually eliminated and its gene transcription turned off, thus rendering it functionally irrelevant in most mature neurons. However, a hand full of brain regions contain fully differentiated neurons that are spared from Sox2 downregulation and retain strong Sox2 expression. One of such regions is the suprachiasmatic nucleus (SCN), that contains the mammalian central circadian clock. The 20,000 clock neurons in the SCN are responsible for interpreting photic signals and orchestrating oscillations in peripheral tissues. In this study, I demonstrated the “unusual” and “non-canonical” roles of Sox2 in these post-mitotic and differentiated clock neurons. By creating a Sox2 gene knockout specifically in the SCN, I found that Sox2 in SCN neurons is pivotal for high-magnitude expression of clock genes and neuropeptides that are critical for circadian rhythm regulation. In addition, the absence of Sox2 in SCN neurons leads to severe and widespread changes in behavioral rhythms. My study also shows that neuronal Sox2 expression is vital for defining the transcriptional landscape of the SCN and promoting its function as the central circadian pacemaker. These severe consequences of Sox2-deficiency observed in adult mutant animals are, at least in part, due to developmental and differentiation defects of the SCN.

Department dc:contributor.department

Cell and Systems Biology

Year dc:date.issued

2021

Author dc:creator

• Cheng, Arthur Hoi Hin

Advisor dc:contributor.advisor

• Cheng, Hai-Ying Mary

• behavior
• circadian rhythms
• RNA sequencing
• SOX2
• stem cell transcription factor
• suprachiasmatic nucleus

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/128388

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128388