1. Biological Clocks, Oscillators, Rhythms… Just generally, Time. or, Of Zeitgebers, Pronking, frq, tim, per, clk, Leeches, …and Other Fun Words.

2. Where we’re going… Examples of oscillators (heart, breathing, pacing neural signals, circadian rhythms, hibernation cycles, cell division cycle) What controls them? Internal vs external driving forces Timing in development

3. Why we need time. 1.Development. When should which cells turn into what? What order should things happen? How do they know when to differentiate? What about life events? (Maturity, etc). 2. Normal, daily life involves cycles. Cell division, metabolism, sleep, hibernation, heart beats, regeneration of cells.

5. Neurospora, a unicellular fungus. It has different cell types.

6. Cycles First. Lots of different “clocks” in most organisms. Can have more or less central control (SCN - superchiasmatic nucleus - in mammals; different organs have different clocks; different feedback loops in even unicellular organisms)

7. Circadian genes Most studied (sleep disorder implications, etc) WC, frq in Neurospora clk, bmal, per, cry in mammals per, tim, cyc, clk in Drosophila These genes are similar, and form similar feedback loops. Several of them are related.

8. Key elements: Something that inhibits itself either directly or indirectly (allows for the delay) Degradation or some other “reset” cue In most cases, the ability to reset to external conditions but to keep functioning without external impetus Outputs that regulate other cell functions

11. Note: control takes place at different stages Transcription Translation Protein functionality Speed of degradation We can tell what’s happening based on which concentrations change (mRNA, protein, etc)

12. What do these clocks regulate? Gene expression! Metabolism! Behavior! Similar mechanisms operate on smaller scales to regulate smooth muscle contraction, neural firing, liver activity, and other processes.

13. External cues can reset the clock Light induced changes in protein conformation (that allow or block other molecules binding) Light induced degradation of molecules Most effective at dawn/dusk usually Other factors that can reset different oscillators: temperature, nutrient concentration, length of day

14. Leech Heartbeats Chemical pathways aren’t the only oscillatory systems in biology. Electrical oscillations (eg in nerves) play a role. Also in development, perhaps. Some nerves inhibit the firing of others in a cyclical way --> regular pattern 2 possible modes; can switch between them

15. Development: we need a way to keep track of time… Oscillators, counters. For example, cells that form the vertebra in embryos may undergo different numbers of oscillations in certain chemicals, which could play a role in differentiation. “Timers”: threshold concentrations that make a process start or stop (can be temperature dependent).

16. Somite formation in embryos. Differentiation may be a result of experiencing different numbers of oscillations in PSM concentration during formation.

17. The Cell Cycle as Timer Cell division  lower concentrations of certain chemicals  cell differentiation Several examples: –Kickstart expression of embryonic genes –Transition from cell division to cell differentiation –Hox gene expression

18. Other examples: -in mice, build up of a certain protein (p27kip1, which blocks transition from G1 to S phase in cell division) eventually stops the cell cycle and leads to differentiation rather than further division

19. Pronking Springboks Another type of electrical coordination/oscillation. All the legs are in phase! http://www.youtube.com/watch?v=8Ba3UxqXiXU

20. Sources http://inls.ucsd.edu/~lev/gene/ http://www.hhmi.org/biointeractive/media/SCN-lg.mov http://www.daviddarling.info/images/cell_cycle.jpg http://ajpregu.physiology.org/cgi/content/abstract/246/6/R847 http://www.fgsc.net/Neurospora/sectionB3.htm http://jn.physiology.org/cgi/content/abstract/91/1/382 http://jn.physiology.org/cgi/reprint/87/3/1572 http://jbr.sagepub.com/cgi/reprint/19/5/414 http://template.bio.warwick.ac.uk/staff/amillar/andrewM/Jo%20Selwood%20site/cogs_of_clock.htm#Negative%20fee dbackhttp://template.bio.warwick.ac.uk/staff/amillar/andrewM/Jo%20Selwood%20site/cogs_of_clock.htm#Negative%20fee dback Olivier Pourquie, “A Biochemical Oscillator Linked to Vertebrate Segmentation.” In G. B. Müller and S. A. Newman, Origination of Organismal Form: beyond the gene in developmental and evolutionary biology. Chapter 11. http://farm2.static.flickr.com/1434/970206932_e41c64ee04.jpg http://images.smarter.com/blogs/clock1.jpg http://mirror-us-ga1.gallery.hd.org/_c/flowers/_more2003/_more09/flower-Holland-Netherlands-RF.jpg.html http://staffwww.fullcoll.edu/tmorris/elements_of_ecology/images/chipmunk_hibernating.jpg http://akvis.com/en/sketch-tutorial/wolf-color- sketch.php&h=336&w=500&sz=30&hl=en&start=2&um=1&tbnid=mrcypLBWAycaYM:&tbnh=87&tb nw=130&prev=/images%3Fq%3Dwolf%26um%3D1%26hl%3Den%26client%3Dfirefox- a%26rls%3Dorg.mozilla:en-US:official%26sa%3DGhttp://akvis.com/en/sketch-tutorial/wolf-color- sketch.php&h=336&w=500&sz=30&hl=en&start=2&um=1&tbnid=mrcypLBWAycaYM:&tbnh=87&tb nw=130&prev=/images%3Fq%3Dwolf%26um%3D1%26hl%3Den%26client%3Dfirefox- a%26rls%3Dorg.mozilla:en-US:official%26sa%3DG http://www.worldmigratorybirdday.org/2007/images/stories/wmbd/alyn_walsh.jpg