Mathematical model of the Drosophila circadian clock: Loop regulation and transcriptional integration

Academic Article

Abstract

  • Eukaryotic circadian clocks include interconnected positive and negative feedback loops. The clock-cycle dimer (CLK-CYC) and its homolog, CLK-BMAL1, are key transcriptional activators of central components of the Drosophila and mammalian circadian networks, respectively. In Drosophila, negative loops include period-timeless and vrille; positive loops include par domain protein 1. Clockwork orange (CWO) is a recently discovered negative transcription factor with unusual effects on period, timeless, vrille, and par domain protein 1. To understand the actions of this protein, we introduced a new system of ordinary differential equations to model regulatory networks. The model is faithful in the sense that it replicates biological observations. CWO loop actions elevate CLK-CYC; the transcription of direct targets responds by integrating opposing signals from CWO and CLK-CYC. Loop regulation and integration of opposite transcriptional signals appear to be central mechanisms as they also explain paradoxical effects of period gain-of-function and null mutations. © 2009 by the Biophysical Society.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Fathallah-Shaykh HM; Bona JL; Kadener S
  • Start Page

  • 2399
  • End Page

  • 2408
  • Volume

  • 97
  • Issue

  • 9