Sleep is an important behavior across diverse species, regulated by conserved signaling pathways. OSAS (obstructive sleep apnea syndrome) is characterized by episodic hypoxia, affecting about 5% of adult American population and may lead to hypertension, if left untreated. In C. elegans post-embryonic development is accompanied by four larval stages [Sulston et al., 1983] that are interrupted by periods of inactivity called lethargus, and has been suggested to represent 'sleep' [Raizen et al., 2008]. The cAMP-CREB pathway has been shown to affect sleep-wake cycle in Drosophila, C. elegans and mammalian systems [Zimmerman et al., 2008], and cGMP dependent protein kinase expression is regulated by Rho and KLF4 [Zeng et al., 2006]. Genetic analysis has suggested the role of LIN-3 and LET-23 (the EGF like-ligand and EGF receptor, respectively) in sleep like behavior in C. elegans [Van Buskirk and Sternberg, 2007]. Overexpression of LIN-3 results in quiescent behavior during periods of normal activity, through the activity of ALA neuron that is regulated by paired (a family of Kruppel like transcription factors) and LIM class of transcription factors CEH17, CEH-14/Chx10, and CEH17/Phox2 through a feedback regulatory pathway [Van Buskirk and Sternberg, 2010]. We have shown the role of KLF-3 in beta oxidation of fatty acids in C. elegans that results in accumulation of fat in intestinal cells in
klf-3(
ok1975) homozygous loss of function mutants, arrested development and poor fecundity [Hashmi et al., 2008; Zhang et al. 2011 submitted], and may also affect sleep cycle by affecting the lethargus timings during larval molts. Interestingly, KLF4 in mammals not only mediates adipogenesis but also regulates kallistatin expression [Shen et al., 2009] that regulates kidney protein expression during episodic hypoxia (EH), by inhibiting vasodilation mediated by kallikrein-Kallistatin signaling pathway [Thonhboonkered et al., 2002]. The sleep regulating
egl-4 gain of function mutation in cyclic GMP also results in the accumulation of fat in the intestine [Raizen et al., 2006]. Thus accumulating results suggest that
klf-3 signaling pathway analysis in C. elegans may elucidate fat utilization (see the abstract by Hashmi et al., this meeting), sleep, and reproductive behavior.