A Conserved Circadian Function for the Neurofibromatosis 1 Gene
Lei Bai,
Yool Lee,
Cynthia T. Hsu,
Julie A. Williams,
Daniel Cavanaugh,
Xiangzhong Zheng,
Carly Stein,
Paula Haynes,
Han Wang,
David H. Gutmann,
Amita Sehgal
Affiliations
Lei Bai
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Yool Lee
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Cynthia T. Hsu
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Julie A. Williams
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Daniel Cavanaugh
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biology, Loyola University, Chicago, IL, USA
Xiangzhong Zheng
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Bloomington Stock Center, Indiana University, Bloomington, IN, USA
Carly Stein
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Paula Haynes
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Han Wang
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; School of Law, University of California, Los Angeles, Los Angeles, CA, USA
David H. Gutmann
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, Washington University, St. Louis, MO, USA
Amita Sehgal
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: Loss of the Neurofibromatosis 1 (Nf1) protein, neurofibromin, in Drosophila disrupts circadian rhythms of locomotor activity without impairing central clock function, suggesting effects downstream of the clock. However, the relevant cellular mechanisms are not known. Leveraging the discovery of output circuits for locomotor rhythms, we dissected cellular actions of neurofibromin in recently identified substrates. Herein, we show that neurofibromin affects the levels and cycling of calcium in multiple circadian peptidergic neurons. A prominent site of action is the pars intercerebralis (PI), the fly equivalent of the hypothalamus, with cell-autonomous effects of Nf1 in PI cells that secrete DH44. Nf1 interacts genetically with peptide signaling to affect circadian behavior. We extended these studies to mammals to demonstrate that mouse astrocytes exhibit a 24-hr rhythm of calcium levels, which is also attenuated by lack of neurofibromin. These findings establish a conserved role for neurofibromin in intracellular signaling rhythms within the nervous system. : Bai et al. show that the gene mutated in the disease Neurofibromatosis 1 is required for maintaining levels or cycling of calcium in circadian neurons in Drosophila and in mammalian cells. These effects likely account for effects of Nf1 on circadian behavior in Drosophila and may be relevant in explaining sleep phenotypes in patients. Keywords: circadian rhythms, neurofibromatosis 1, Drosophila, peptide signaling, cycling of calcium, mouse astrocytes
