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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3416-3426
Number of pages11
JournalCell Reports
Volume22
Issue number13
DOIs
StatePublished - Mar 27 2018

Keywords

  • Drosophila
  • circadian rhythms
  • cycling of calcium
  • mouse astrocytes
  • neurofibromatosis 1
  • peptide signaling

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  • Cite this

    Bai, L., Lee, Y., Hsu, C. T., Williams, J. A., Cavanaugh, D., Zheng, X., Stein, C., Haynes, P., Wang, H., Gutmann, D. H., & Sehgal, A. (2018). A Conserved Circadian Function for the Neurofibromatosis 1 Gene. Cell Reports, 22(13), 3416-3426. https://doi.org/10.1016/j.celrep.2018.03.014