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In 2003, Steven Reppert began investigating the functional and evolutionary properties of the cryptochrome (CRY) protein in the Monarch Butterfly. Reppert has identified two Cry genes in monarchs, ds''Cry1'' and ds''Cry2''<ref>{{cite journal|last=Reppert|first=SM|coauthors=Haisun Zhu, Quan Yuan, Oren Froy, Amy Casselman|title=The two CRYs of the butterfly|journal=Current Biology|date=6 Dec, 2005|year=2005|month=December|volume=15|issue=23|page=R953|pages=R954|pmid=16332522|url=http://www.cell.com/current-biology/retrieve/pii/S0960982205014053#}}</ref>. He work demonstrated that dsCRY1 is functionally analogous to the blue light photoreceptor dCRY necessary for [[Entrainment_(chronobiology)|photoentrainment]] in drosophila. He also demonstrated that dsCRY2 was functionally analogous to vertebral mCRY, acting as a transcriptional [[repressor]] in the [[Circadian_clock#Transcriptional_and_translational_control|circadian clock transcriptional translation feedback loop]]. These data propose the existence of a novel [[circadian clock]] unique to non-drosophilid insects that possess mechanisms characteristic of both drosophilian and mammalian clocks<ref>{{cite journal|last=Reppert|first=SM
In 2003, Steven Reppert began investigating the functional and evolutionary properties of the cryptochrome (CRY) protein in the Monarch Butterfly. Reppert has identified two Cry genes in monarchs, ds''Cry1'' and ds''Cry2''<ref>{{cite journal|last=Reppert|first=SM|coauthors=Haisun Zhu, Quan Yuan, Oren Froy, Amy Casselman|title=The two CRYs of the butterfly|journal=Current Biology|date=6 Dec, 2005|year=2005|month=December|volume=15|issue=23|page=R953|pages=R954|pmid=16332522|url=http://www.cell.com/current-biology/retrieve/pii/S0960982205014053#}}</ref>. He work demonstrated that dsCRY1 is functionally analogous to the blue light photoreceptor dCRY necessary for [[Entrainment_(chronobiology)|photoentrainment]] in drosophila. He also demonstrated that dsCRY2 was functionally analogous to vertebral mCRY, acting as a transcriptional [[repressor]] in the [[Circadian_clock#Transcriptional_and_translational_control|circadian clock transcriptional translation feedback loop]]. These data propose the existence of a novel [[circadian clock]] unique to non-drosophilid insects that possess mechanisms characteristic of both drosophilian and mammalian clocks<ref>{{cite journal|last=Reppert|first=SM
|coauthors=Haisun Zhu, Ivo Sauman, Quan Yuan, Amy Casselman, Myai Emery-Le, Patrick Emery
|coauthors=Haisun Zhu, Ivo Sauman, Quan Yuan, Amy Casselman, Myai Emery-Le, Patrick Emery
|title=Cryptochromes Define a Novel Circadian Clock Mechanism in Monarch Butterflies That May Underlie Sun Compass Navigation|journal=PLOS|date=Jan 8, 2008|volume=6|issue=1|page=e4|pmid=18184036|url=http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060004}}</ref>. His research also identified a ds''Cry2'' mRNA positive neural circuit that synapse at the central complex, the perceived site of the sun compass in monarchs, implying that ds''Cry2'' may mediate the internal circadian component of monarch navigation
|title=Cryptochromes Define a Novel Circadian Clock Mechanism in Monarch Butterflies That May Underlie Sun Compass Navigation|journal=PLOS|date=Jan 8, 2008|volume=6|issue=1|page=e4|pmid=18184036|url=http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060004}}</ref>. His research also identified a ds''Cry2'' mRNA positive neural circuit that synapses at the central complex, the perceived site of the sun compass in monarchs, implying that ds''Cry2'' may mediate the internal circadian clock component of monarch navigation
<ref>{{cite journal
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Revision as of 20:53, 13 April 2013

Steven M. Reppert is an American neuroscientist who is known for his contributions to the fields of circadian biology and neuroethology. His research has focused largely on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He is currently the founding chair of the Department of Neurobiology and the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School.

Background

Reppert received his BS and MD (with Distinction) from the University of Nebraska College of Medicine and was elected as a medical student to the Alpha Omega Alpha Honor Medical Society. He did an internship and residency in Pediatrics at the Massachusetts General Hospital and postdoctoral work in neuroendocrinology at the National Institute of Child Health and Human Development in Bethesda, Maryland with David C. Klein. Reppert was on the faculty at the Massachusetts General Hospital and Harvard Medical School beginning in 1979 and was promoted to Professor in 1993; he directed the Laboratory of Developmental Chronobiology at the Massachusetts General Hospital from 1983 to 2001, when he moved to the University of Massachusetts Medical School.[1]

Reppert was a Charles King Trust Research Fellow from 1981 to 1983 and an Established Investigator of the American Heart Association from 1985 to 1990. He has been a recipient of the E. Mead Johnson Award for Outstanding Research Contributions (1989)[2] and the NIH-NICHD MERIT Award (1992–2002). From 2002 to 2004, he served as president of the Society for Research on Biological Rhythms.[3] He is an elected fellow of the American Association for the Advancement of Science.[4] Reppert has published more than 150 papers in peer-reviewed journals and is the principal inventor on seven patents derived from his research.[5]

Research

The research contributions of Reppert and colleagues include defining the field of fetal circadian clocks,[6][7][8] discovering that the circadian clock mechanism in the mammalian suprachiasmatic nucleus (SCN), the site of the master brain clock, is cell autonomous (i.e., contained within single cells),[9][10] and cloning and functionally defining a family of melatonin receptors (G-protein coupled receptors for the pineal hormone).[11][12] Reppert’s group identified a molecular mechanism for regulating clock-controlled genes in mammals,[13] discovered the function of cryptochromes within the mammalian circadian clock,[14][15] and defined interlocking transcriptional feedback loops in the mouse SCN.[16][17] In 2006, his team made the unexpected finding that CLOCK, a transcription factor believed to be an essential component of the molecular clockwork mechanism, is not necessary for SCN clock function.[18][19][20] They went on to show that a related transcription factor, NPAS2 (MOP4), can functionally substitute for CLOCK in the SCN[21][22] to regulate behavioral circadian rhythms.

Monarch Butterfly Migration Research

Since 2002, Reppert and co-workers have pioneered the study of the biological basis of monarch butterfly migration.[23][24] Each fall, millions of monarchs from Eastern United States and Southeastern Canada migrate over 4000km to overwinter in roosts in Central Mexico.[25] Previous research has found that monarch migration is not a learned activity since migrants going south are at least two generations removed from previous generations of migrants.[26] Thus, monarch migration must have some biological basis that aids navigation.

Reppert and colleagues have focused on a novel circadian clock mechanism and its role in time-compensated sun compass orientation, a major navigational strategy that butterflies use during their fall migration, first described byKarl von Frisch in 1967 in foraging honeybees and by Gustav Kramer in 1957 in migratory birds. Monarch butterflies must re-calibrate their navigation using environmental factors. Their circadian clock is standardized to local time by dawn and dusk while their Sun compass may be calibrated by geomagnetic forces, visualizing certain landmarks, barometric pressure, and prevailing wind direction.[27]

Reppert and colleagues have pioneered research demonstrating the importance of circadian clock in regulating the time-compensated component of flight orientation. Reppert and colleagues conducted a clock-shift experiment to demonstrate how the circadian clock interacts with the Sun compass in order to enable migrants to maintain a southwesterly flight direction as the Sun moves daily.[28] They exposed one group of migrants to 12 hours of light from 7:00AM to 7:00PM, a standard fall lighting schedule, followed by 12 hours of darkness. They exposed another group to 12 hours of light 6 hours earlier between 1:00AM and 1:00PM. Using an outdoor flight simulator with the migrants tethered, they found that the migrants with the standard light schedule oriented southwest as expected, while the migrants exposed to a light schedule 6 hours earlier oriented to the southeast, demonstrating a circadian shift in the time-compensated sun compass. Reppert and colleagues then exposed the previous migrant groups to constant light, which is known to disrupt circadian timing, in order to test if the circadian clock is necessary for successful migration. They found that migrants exposed to the standard light schedule, and those exposed to the earlier light schedule did not differ in orientation direction, which indicated a loss of circadian control and demonstrated that a functioning circadian clock is necessary for successful migration.

Repperts lab has also provided new information on the sunlight-dependent parameters used for navigation.[29] He found that Monarch butterflies utilize patterns of polarized light as a sun compass cue in a time-compensated manner. Using tethered migrant butterflies in an outdoor flight simulator, Reppert found that the oreintation of flight was dependent on the angle of polarized light. This significant finding provides insight into how migrating monarchs can navigate under various atmospheric conditions.

Steven Reppert's lab has published numerous papers detailing their findings:

  • Using previous electrophysiological studies of locusts, as well as careful mapping of the monarch butterflies brain, Reppert has indicated that the “central complex (CX) is likely the site of the actual sun compass.” [30]
  • Reppert’s lab expanded upon the previous postulations of Fred Urquhart which stated that antennae may play a role in monarch migration. In 2009 Reppert’s lab reported that, despite previous assumptions that the clock is located in the brain, there actually are antennal clocks, and “the antennae are necessary for proper time-compensated sun compass orientation in migratory monarch butterflies.” [31]
  • Studies of antennal clocks were expanded upon in 2012, concluding that only a single antenna is sufficient for sun compass orientation. They demonstrated this by painting a single antennae black to cause discordant light exposure between the two antennae, and found that the single not-painted antennae is still sufficient. “All four clock genes (per, tim, cry1, and cry2) were expressed in the different areas of the antennae studied, suggesting that “light entrained circadian clocks are distributed throughout the length of the monarch butterfly antenna.” [32]
  • In 2011, Reppert and colleagues presented the initial draft sequence of the monarch butterfly genome and a set 16,866 protein-coding genes. This is the first characterized genome of a butterfly and of a long-distance migratory species.[33][34][35]
  • In 2012, Reppert and colleagues established MonarchBase, an integrated database for Danaus plexippus' genome. The goal of the project was to make genomic and proteomic information about monarch butterflies accessible to biological and lepidopteran communities. [36]
  • The monarch clockwork model, which has both drosophila-like and mammalian-like aspects, is unique because it utilizes two distinct CRYPTOCHROME (CRY) proteins. As presented in a 2010 paper[37] , the clock mechanism, on a gene/protein level, operates as follows:
    • There is an autoregulatory transcription feedback loop in which heterodimers of CLOCK (CLK) and CYCLE (CYC) form and drive the transcription of the period (per) , timeless (tim), and cryptochrome2 (cry2) genes;
    • TIM (T), PER (P), and CRY2 (C2) proteins are translated and move from the nucleus to the cytoplasm where they form complexes;
    • 24 hours later CRY2 returns to the nucleus, inhibiting CLK:CYC transcription;
    • Meanwhile PER is progressively phosphorylated, which may aid CRY2 translocation into the nucleus;
    • And CRYPTOCHROME1 (CRY1, C1) protein is a circadian photoreceptor which when exposed to light, causes TIM degradation, allowing light to gain access to the central clock mechanism for photic entrainment.


In 2003, Steven Reppert began investigating the functional and evolutionary properties of the cryptochrome (CRY) protein in the Monarch Butterfly. Reppert has identified two Cry genes in monarchs, dsCry1 and dsCry2[38]. He work demonstrated that dsCRY1 is functionally analogous to the blue light photoreceptor dCRY necessary for photoentrainment in drosophila. He also demonstrated that dsCRY2 was functionally analogous to vertebral mCRY, acting as a transcriptional repressor in the circadian clock transcriptional translation feedback loop. These data propose the existence of a novel circadian clock unique to non-drosophilid insects that possess mechanisms characteristic of both drosophilian and mammalian clocks[39]. His research also identified a dsCry2 mRNA positive neural circuit that synapses at the central complex, the perceived site of the sun compass in monarchs, implying that dsCry2 may mediate the internal circadian clock component of monarch navigation [40].

In 2008, Reppert discovered the necessity of drosophila dCry for light-dependent magnetoreception responses in drosophila. He also showed that magnetic sensation requires UVA/blue light, the spectrum corresponding with the action spectrum of CRY [41]. These data were first to involve Cry as a component of the input pathway or the chemical based pathway of magnetoreception. Applying these finding to his work with monarchs, Reppert identified that both Monarch dsCRY1 and dsCRY2 proteins, when transgenically expressed in cry° flies, successfully restore magnetoreception function [42]. These results propose the involvement of a Cry-mediated magnetosensitivity system in monarchs as an additional property of navigation. In 2011, Reppert also discovered that hCry2 can substitute as a functional magnetoreceptor in Cry deficient flies, a discovery that warrants additional research into magnetosensitivity in humans and possible influences of magnetic fields on human visual function [43].

References

  1. ^ http://www.umassmed.edu/neuroscience/faculty/reppert.cfm
  2. ^ http://www.aps-spr.org/spr/Awards/EMJ.htm
  3. ^ http://www.srbr.org/Pages/past_meetings.aspx
  4. ^ http://www.aaas.org/aboutaaas/fellows/
  5. ^ http://www.patentbuddy.com/Inventor/Reppert-Steven-M/1437735
  6. ^ Reppert SM, Schwartz WJ (1983). "Maternal coordination of the fetal biological clock in utero". Science. 220 (4600): 969–71. doi:10.1126/science.6844923. PMID 6844923. {{cite journal}}: Unknown parameter |month= ignored (help)
  7. ^ "Scientists find unborn rats can sense time". Lawrence, KS: Lawrence Journal-World. Associated Press. May 20, 1983. p. 23.
  8. ^ Klinkenborg, Verlyn (5 January 1997). "Awakening to Sleep". The New York Times Magazine. New York.
  9. ^ Welsh DK, Logothetis DE, Meister M, Reppert SM (1995). "Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms". Neuron. 14 (4): 697–706. doi:10.1016/0896-6273(95)90214-7. PMID 7718233. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Caldwell, Mark (July 1999). "Mind Over Time". DISCOVER Magazine. Retrieved 12 January 2010.
  11. ^ Reppert SM, Weaver DR, Godson C (1996). "Melatonin receptors step into the light: cloning and classification of subtypes". Trends in Pharmacological Sciences. 17 (3): 100–2. doi:10.1016/0165-6147(96)10005-5. PMID 8936344. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Barinaga M (1997). "How jet-lag hormone does double duty in the brain". Science. 277 (5325): 480. doi:10.1126/science.277.5325.480. PMID 9254421. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ Jin X, Shearman LP, Weaver DR, Zylka MJ, de Vries GJ, Reppert SM (1999). "A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock". Cell. 96 (1): 57–68. doi:10.1016/S0092-8674(00)80959-9. PMID 9989497. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Kume K, Zylka MJ, Sriram S; et al. (1999). "mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop". Cell. 98 (2): 193–205. doi:10.1016/S0092-8674(00)81014-4. PMID 10428031. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Barinaga M (1999). "Circadian rhythms. CRY's clock role differs in mice, flies". Science. 285 (5427): 506–7. doi:10.1126/science.285.5427.506. PMID 10447476. {{cite journal}}: Unknown parameter |month= ignored (help)
  16. ^ Shearman LP, Sriram S, Weaver DR; et al. (2000). "Interacting molecular loops in the mammalian circadian clock". Science. 288 (5468): 1013–9. doi:10.1126/science.288.5468.1013. PMID 10807566. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Barinaga M (2000). "Circadian rhythms. Two feedback loops run mammalian clock". Science. 288 (5468): 943–4. doi:10.1126/science.288.5468.943a. PMID 10841707. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ Debruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM. (2006). "A clock shock: mouse CLOCK is not required for circadian oscillator function". Neuron. 50 (3): 465–77. doi:10.1016/j.neuron.2006.03.041. PMID 16675400. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Collins B, Blau J. (2006). "Keeping Time without a Clock". Neuron. 50 (3): 348–50. doi:10.1016/j.neuron.2006.04.022. PMID 16675389. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Miller G (2006). "Despite Mutated Gene, Mouse Circadian Clock Keeps on Ticking". Science. 312 (5774): 673. doi:10.1126/science.312.5774.673. PMID 16675672. {{cite journal}}: Unknown parameter |month= ignored (help)
  21. ^ DeBruyne JP, Weaver DR, Reppert SM. (2007). "CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock". Nat Neurosci. 10 (5): 543–5. doi:10.1038/nn1884. PMC 2782643. PMID 17417633. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Asher G, Schibler U. (2006). "A CLOCK-less clock". Trends Cell Biol. 16 (11): 547–9. doi:10.1016/j.tcb.2006.09.005. PMID 16996737. {{cite journal}}: Unknown parameter |month= ignored (help)
  23. ^ Kyriacou CP (2009). "Clocks, cryptochromes and Monarch migrations". Journal of Biology. 8 (6): 55. doi:10.1186/jbiol153. PMC 2737371. PMID 19591650.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Reppert SM, Gegear RJ, Merlin C (2010). "Navigational mechanisms of migrating monarch butterflies". Trends in Neurosciences. 33 (9): 399–406. doi:10.1016/j.tins.2010.04.004. PMC 2929297. PMID 20627420.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Reppert, Steven (2010). "Navigational Mechanisms of Migrating Monarch Butterflies". Trends in Neurosciences. 33 (9): 399–406. doi:10.1016/j.tins.2010.04.004. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  26. ^ Brower, Lincoln (1996). "Monarch Butterfly Orientation: Missing Pieces of a Magnificent Puzzle". Journal of Experimental Biology. 199: 93–103.
  27. ^ Merlin, Christine (2009). "Antennal Circadian Clocks Coordinate Sun Compass Orientation in Migratory Monarch Butterflies". Science. 325 (1700–1704). doi:10.1126/science.1176221. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  28. ^ Froy, Oren (2003). "Illuminating the Circadian Clock in Monarch Butterfly Migration". Science. 300: 1303–1305. doi:10.1126/science.1084874. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ Reppert, Steven (2004). "Polarized Light Helps Monarch Butterflies Navigate". Current Biology. 14: 155–158. doi:10.1016/j.cub.2003.12.034. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  30. ^ Heinze, S (2013). "Anatomical basis of sun compass navigation II: The neuronal composition of the central complex of the monarch butterfly". Comp Neurol. 521: 267-298. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  31. ^ Guerra, P (2012). "Discordant timing between antennae disrupts sun compass orientation in migratory monarch butterflies". Nat Commun. 3: 958. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  32. ^ Merlin, C (2012). "Discordant timing between antennae disrupts sun compass orientation in migratory monarch butterflies". Nat Commun. 3: 958. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  33. ^ Zhan S, Merlin C, Boore JL, Reppert SM (2011). "The Monarch Butterfly Genome Yields Insights into Long-Distance Migration". Cell. 147 (5): 1171–85. doi:10.1016/j.cell.2011.09.052. PMID 22118469. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  34. ^ Stensmyr MC, Hansson BS (2011). "A Genome Befitting a Monarch". Cell. 147 (5): 970–2. doi:10.1016/j.cell.2011.11.009. PMID 22118454. {{cite journal}}: Unknown parameter |month= ignored (help)
  35. ^ Johnson, Carolyn Y. (23 November 2011). "Monarch butterfly genome sequenced". The Boston Globe. Boston, MA. Retrieved 9 January 2012.
  36. ^ Zhan, S (9). "MonarchBase: the monarch butterfly genome database". Nucleic Acids Research Advance Access: 1–6. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  37. ^ Reppert, SM (2010). "Navigational mechanisms of migrating monarch butterflies". Trends in Neurosciences. 33: 391–434. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  38. ^ Reppert, SM (6 Dec, 2005). "The two CRYs of the butterfly". Current Biology. 15 (23): R953. PMID 16332522. {{cite journal}}: Check date values in: |date= (help); More than one of |pages= and |page= specified (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  39. ^ Reppert, SM (Jan 8, 2008). "Cryptochromes Define a Novel Circadian Clock Mechanism in Monarch Butterflies That May Underlie Sun Compass Navigation". PLOS. 6 (1): e4. PMID 18184036. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  40. ^ Reppert, SM (8 Jan 2008). "Cryptochromes Define a Novel Circadian Clock Mechanism in Monarch Butterflies That May Underlie Sun Compass Navigation". PLOS. 6 (1): e4. PMID 18184036. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  41. ^ Reppert, SM (21 August 2008). "Cryptochrome mediates light-dependent magnetosensitivity in Drosophila". Nature. 454: 1014-1018. PMID 18641630. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  42. ^ Reppert, SM (11 Feb 2010). "Animal cryptochromes mediate magnetoreception by an unconventional photochemical mechanism". Nature. 10.1038/nature08719. 463: 804-808. PMID 20098414. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  43. ^ Reppert, SM (21 June 2011). "Human cryptochrome exhibits light-dependent magnetosensitivity". Nature Communications. 356. 2. PMID 21694704. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

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