Development, Maturation, and Necessity of Transcription Factors in the Mouse Suprachiasmatic Nucleus

Apr 29, 2011The Journal of neuroscience : the official journal of the Society for Neuroscience

Growth, development, and importance of gene regulators in the mouse brain’s internal clock

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Abstract

The conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the suprachiasmatic nucleus (SCN).

The SCN is identified as the master circadian clock in mammals, coordinating a nearly 24-hour rhythm.
Transcription factor expression in the SCN exhibits specific changes during prenatal and postnatal development.
Global and regional patterns of transcription factor expression were observed extending into adulthood.
The SCN originates from a specific area of the neuroepithelium that expresses developmental genes such as Six3 and Six6.
RORα was found to be expressed during SCN development and adulthood but did not affect SCN peptide expression or localization.

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The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORα and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORα function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior.

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Development, Maturation, and Necessity of Transcription Factors in the Mouse Suprachiasmatic Nucleus

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