Pigment-Dispersing Factor (PDF) Has Different Effects on Drosophila 's Circadian Clocks in the Accessory Medulla and in the Dorsal Brain

Abstract

The neuropeptide pigment-dispersing factor (PDF) is a key transmitter in the circadian clock of Drosophila melanogaster. Here we studied the rhythmic behavior of neural mutants with modified arborizations of the large PDF neurons. In sine oculis¹ (so¹ ) mutants we found a higher density of PDF fibers in the fly's pacemaker center, the accessory medulla. These flies exhibited a significantly longer period (24.6 h) than control flies. When PDF levels were elevated to very high levels in the dorsal brain as true for so^mda mutants and small optic lobes;so¹ double mutants (sol¹;so¹ ), a short-period component split off the long period in behavioral rhythmicity. The short period became shorter the higher the amount of PDF in this brain region and reached a value of ~21 h. The period alterations were clearly dependent on PDF, because so¹;Pdf 01 and so^mda;Pdf 01 double mutants showed a single free-running component with a period similar to Pdf 01 mutants (~22.5 h) and significantly longer than the short period of so^mda mutants. These observations indicate that PDF feeds back on the clock neurons and changes their period. Obviously, PDF lengthens the period of some clock neurons and shortens that of others.

Keywords

Key words pigment dispersing factor internal desynchronization neural mutants accessory medulla

References

Aton SJ , Colwell CS , Harmar AJ , Waschek J. , and Herzog ED (2005) Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8:476-483.

Bachleitner W. , Kempinger L. , Wülbeck C. , Rieger D. , and Helfrich-Förster C. (2007) Moonlight shifts the endogenous clock of Drosophila melanogaster. Proc Natl Acad Sci U S A 104:3538-3543.

Blanchardon E. , Grima B. , Klarsfeld A. , Chelot E. , Hardin PE , Preat T. , and Rouyer F. (2001) Defining the role of Drosophila lateral neurons in the control of circadian rhythms in motor activity and eclosion by targeted genetic ablation and PERIOD protein overexpression. Eur J Neurosci 13:871-888.

Cheyette BN , Green PJ , Martin K. , Garren H. , Hartenstein V. , and Zipursky SL (1994) The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12:977-996.

de la Iglesia HO , Meyer J. , and Schwartz WJ (2004) Forced desynchronization of dual circadian oscillators within the rat suprachiasmatic nucleus. Curr Biol 14:796-800.

Delaney SJ , Hayward DC , Barleben F. , Fischbach KF , and Miklos GL (1991) Molecular cloning and analysis of small optic lobes, a structural brain gene of Drosophila melanogaster. Proc Natl Acad Sci U S A 88:7214-7218.

Dircksen H. , Zahnow CA , Gaus G. , Keller R. , Rao KR , and Riehm JP (1987) The ultrastructure of nerve endings containing pigment-dispersing hormone (PDH) in crustacean sinus glands: identification by an antiserum against a synthetic PDH. Cell Tissue Res 250:377-387.

Fischbach KF (1983) Neural cell types surviving congenital sensory deprivation in the optic lobes of Drosophila melanogaster. Dev Biol 95:1-18.

Fischbach KF and Lyly-Hunerberg I. (1983) Genetic dissection of the anterior optic tract of Drosophila melanogaster. Cell Tissue Res 231:551-563.

10.

Fischbach KF and Technau G. (1984) Cell degeneration in the developing optic lobes of the sine oculis and small-optic-lobes mutants of Drosophila melanogaster . Dev Biol 104:219-239.

11.

Glaser WR (1978) Varianzanalyse. Stuttgart: Gustav Fischer.

12.

Grima B. , Chelot E. , Xia R. , and Rouyer F. (2004) Morning and evening peaks of activity rely on different clock neurons of the Drosophila brain. Nature 431:869-873.

13.

Hamasaka Y. and Nässel DR (2006) Mapping of serotonin, dopamine, and histamine in relation to different clock neurons in the brain of Drosophila. J Comp Neurol 494:314-330.

14.

Hardin PE (2005) The circadian timekeeping system of Drosophila . Curr Biol 15:R714-722.

15.

Helfrich C. (1986) Role of the optic lobes in the regulation of the locomotor activity rhythm of Drosophila melanogaster: Behavioral analysis of neural mutants. J Neurogenet 3:321-343.

16.

Helfrich-Förster C. (1997) Development of pigment-dispersing hormone-immunoreactive neurons in the nervous system of Drosophila melanogaster. J Comp Neurol 380:335-354.

17.

Helfrich-Förster C. (1998) Robust circadian rhythmicity of Drosophila melanogaster requires the presence of lateral neurons: A brain-behavioral study of disconnected mutants. J Comp Physiol A 182:435-453.

18.

Helfrich-Förster C. (2004) The circadian clock in the brain: A structural and functional comparison between mammals and insects. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 190:601-613.

19.

Helfrich-Förster C. and Homberg U. (1993) Pigment-dispersing hormone-immunoreactive neurons in the nervous system of wild-type Drosophila melanogaster and of several mutants with altered circadian rhythmicity. J Comp Neurol 337:177-190.

20.

Helfrich-Förster C. , Shafer OT , Wülbeck C. , Grieshaber E. , Rieger D. , and Taghert P. (2007) Development and morphology of the clock-gene-expressing lateral neurons of Drosophila melanogaster. J Comp Neurol 500:47-70.

21.

Helfrich-Förster C. , Täuber M. , Park JH , Mühlig- Versen M. , Schneuwly S. , and Hofbauer A. (2000) Ectopic expression of the neuropeptide pigment-dispersing factor alters behavioral rhythms in Drosophila melanogaster. J Neurosci 20:3339-3353.

22.

Helfrich-Förster C, Winter C, Hofbauer A, Hall JC, and Stanewsky R (2001) The circadian clock of fruit flies is blind after elimination of all known photoreceptors. Neuron 30:349-261.

23.

Inagaki N. , Honma S. , Ono D. , Tanahashi Y. , and Honma K. (2007) Separate oscillating cell groups in mouse suprachiasmatic nucleus couple photoperiodically to the onset and end of daily activity. Proc Natl Acad Sci U S A 104:7664-7669.

24.

Jagota A. , Iglesia HO , and Schwartz WJ (2000) Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro. Nature Neurosci 3:372-376.

25.

Kaneko M. , Park JH , Cheng Y. , Hardin PE , and Hall JC (2000) Disruption of synaptic transmission or clock-gene-product oscillations in circadian pacemaker cells of Drosophila cause abnormal behavioral rhythms. J Neurobiol 43:207-233.

26.

Lin Y. , Stormo GD , and Taghert PH (2004) The neuropeptide pigment-dispersing factor coordinates pacemaker interactions in the Drosophila circadian system. J Neurosci 24:7951-7957.

27.

Lowrey P. l and Takahashi JS (2004) Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet 5:407-441.

28.

Malpel S. , Klarsfeld A. , and Rouyer F. (2002) Larval optic nerve and adult extra-retinal photoreceptors sequentially associate with clock neurons during Drosophila brain development . Development 129:1443-1453.

29.

Maywood ES , Reddy AB , Wong GK , O'Neill JS , O'Brien JA , McMahon DG , Harmar AJ , Okamura H. , and Hastings MH (2006) Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16:599-605.

30.

Meinertzhagen IA and Pyza E. (1999) Neurotransmitter regulation of circadian structural changes in the fly's visual system. Microsc Res Tech 45:96-105.

31.

Murad A. , Emery-Le M. , and Emery P. (2007) A subset of dorsal neurons modulates circadian behavior and light responses in Drosophila. Neuron 53:689-701.

32.

Nässel DR and Homberg U. (2006) Neuropeptides in interneurons of the insect brain . Cell Tissue Res 326:1-24.

33.

Nitabach MN , Blau J. , and Holmes TC (2002) Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell 109:485-495.

34.

Nitabach MN , Wu Y. , Sheeba V. , Lemon WC , Strumbos J. , Zelensky PK , White BH , and Holmes TC (2006) Electrical hyperexcitation of lateral ventral pacemaker neurons desynchronizes downstream circadian oscillators in the fly circadian circuit and induces multiple behavioral periods. J Neurosci 26:479-489.

35.

Park D. and Griffith LC (2006) Electrophysiological and anatomical characterization of PDF-positive clock neurons in the intact adult Drosophila brain. J Neurophysiol 95:3955-3960.

36.

Park JH , Helfrich-Förster C. , Lee G. , Liu L. , Rosbash M. , and Hall JC (2000) Differential regulation of circadian pacemaker output by separate clock genes in Drosophila. Proc Natl Acad Sci U S A 97:3608-3613.

37.

Peng Y. , Stoleru D. , Levine JD , Hall JC , and Rosbash M. (2003) Drosophila free-running rhythms require intercellular communication. PLoS Biol 1:E13.

38.

Petri B. and Stengl M. (1997) Pigment-dispersing hormone shifts the phase of the circadian pacemaker of the cockroach Leucophaea maderae. J Neurosci 17:4087-4093.

39.

Petri B. and Stengl M. (2001) Phase response curves of a molecular model oscillator: implications for mutual coupling of paired oscillators. J Biol Rhythms 16:125-141.

40.

Picot M. , Cusumano P. , Klarsfeld A. , Ueda R. , and Rouyer F. (2007) Light activates output from evening neurons and inhibits output from morning neurons in the Drosophila circadian clock. PLoS Biol 5:e315.

41.

Pittendrigh CS and Daan S. (1976) A functional analysis of circadian pacemakers in nocturnal rodents. V. Pacemaker structure: a clock for all seasons. J Comp Physiol A 106:333-355.

42.

Pyza E. and Meinertzhagen IA (1998) Neurotransmitters alter the numbers of synapses and organelles in photoreceptor terminals in the lamina of the housefly, Musca domestica. J Comp Physiol A 183:719-727.

43.

Renn SC , Park JH , Rosbash M. , Hall JC , and Taghert PH (1999) A Pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99:791-802.

44.

Rieger D. , Shafer OT , Tomioka K. , and Helfrich-Förster C. (2006) Functional analysis of circadian pacemaker neurons in Drosophila melanogaster. J Neurosci 26:2531-2543.

45.

Schneider NL and Stengl M. (2005) Pigment-dispersing factor and GABA synchronize cells of the isolated circadian clock of the cockroach Leucophaea maderae . J Neurosci 25:5138-5147.

46.

Serikaku MA and O' Tousa JE (1994) sine oculis is a homeobox gene required for Drosophila visual system development. Genetics 138:1137-1150.

47.

Shafer OT , Kim DJ , Nikolaev VO , Lohse MJ , and Taghert PH (2008) Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of Drosophila revealed by real-time cyclic AMP imaging. Neuron 58:223-237.

48.

Shafer OT , Levine JD , Truman JW , and Hall JC (2004) Flies by night: Effects of changing day length on Drosophila's circadian clock. Curr Biol 14:424-432.

49.

Shafer OT , Rosbash M. , and Truman JW (2002) Sequential nuclear accumulation of the clock proteins period and

50.

timeless in the pacemaker neurons of Drosophila melanogaster. J Neurosci 22:5946-5954.

51.

Sheeba V. , Kaneko M. , Sharma VK , and Holmes TC (2008) The Drosophila circadian pacemaker circuit: pas de deux or tarantella? Crit Rev Biochem Molr Biol 43:37-61.

52.

Sheeba V. , Sharma VK , Gu H. , Chou YT , O'Dowd DK , and Holmes TC (2008) Pigment dispersing factor-dependent and -independent circadian locomotor behavioral rhythms. J Neurosci 28:217-227.

53.

Shinohara K. , Honma S. , Katsuno Y. , Abe H. , and Honma K. (1995) Two distinct oscillators in the rat suprachiasmatic nucleus in vitro. Proc Natl Acad Sci U S A 92:7396-7400.

54.

Steller H. , Fischbach KF , and Rubin GM (1987) Disconnected: a locus required for neuronal pathway formation in the visual system of Drosophila. Cell 50:1139-1153.

55.

Stoleru D. , Nawathean P. , Fernández MP , Menet JS , Ceriani MF , and Rosbash M. (2007) The Drosophila circadian network is a seasonal timer. Cell 129:207-219.

56.

Stoleru D. , Peng Y. , Agosto J. , and Rosbash M. (2004) Coupled oscillators control morning and evening locomotor behaviour of Drosophila. Nature 431:862-868.

57.

Stoleru D. , Peng Y. , Nawathean P. , and Rosbash M. (2005) A resetting signal between Drosophila pacemakers synchronizes morning and evening activity. Nature 438:238-242.

58.

Taghert PH and Shafer OT (2006) Mechanisms of clock output in the Drosophila circadian pacemaker system. J Biol Rhythms 21:445-457.

59.

Tix S. , Minden JS , and Technau GM (1989) Pre-existing neuronal pathways in the developing optic lobes of Drosophila. Development 105:739-746.

60.

Veleri S, Brandes C, Helfrich-Förster C, Hall JC, and Stanewsky R (2003) A self-sustaining, light-entrainable circadian oscillator in the Drosophila brain. Curr Biol 13:1758-1767.

61.

Vosko AM , Schroeder A. , Loh DH , and Colwell CS (2007) Vasoactive intestinal peptide and the mammalian circadian system. Gen Comp Endocrinol 152:165-175.

62.

Wu Y. , Cao G. , and Nitabach MN (2008) Accelerated free-running cellular oscillation of non-LNv clock neurons in the absence of LNv electrical activity. J Biol Rhythms 23:117-128.

63.

Yang Z. and Sehgal A. (2001) Role of molecular oscillations in generating behavioral rhythms in Drosophila. Neuron 29:453-467.

64.

Yoshii T. , Funada Y. , Ibuki-Ishibashi T. , Matsumoto A. , Tanimura T. , and Tomioka K. (2004) Drosophila cryb mutation reveals two circadian clocks that drive locomotor rhythm and have different responsiveness to light . J Insect Physiol 50:479-488.