Dictyostelium Chemotaxis

How cells know where to go? Signal Detection and Processing at the Microorganism LevelHerbert LevineUCSD Center for Theoretical Biological Physics (NSF)

Outline:Experiments on chemotactic response in DictyosteliumSignal versus noise in gradient sensingNonlinear amplification via signal transductionCell motility mechanics

*Work also supported by NIGMS P01* Collaboration between 2 bio labs, 1 exp phys lab, and a theory group

1Cells know where to go

Wild-type leukocyte response to fin wound

Matthias et al(2006)Cells can bias their motility machinery based on detecting signals;Much of the time, these signals are diffusing chemicals, but cells can also use mechanical cues

Applications to immune response, wound healing, cancer metastasis2Close-up view of chemotaxisDictybase Website http://dictybase.org/index.htmlCell moves about one cell diameter per minuteDecision-making maintains flexibility (limited hysteresis)

We work on chemotaxis in a model organism, the Dictyostelium amoeba

simplified signalingavailability of genetics toolsease of experimentschemotaxis is crucial for survival

3Questions for theoryCan one predict macroscopic measures of cell motility given the space-time course of an applied signal and (possibly) the cell historyCell speed, directional persistence, chemotactic indexNot just averages, but also distributionsNot just wild-type, but also mutant strainsWe will tackle this problem in stagesSensing of the signalMaking the chemotactic decisionDriving the cells acto-myosin motor4

5Mutual InformationSensing is done roughly 50K receptors, each with a binding constant of 30nM.How much information do we get about a parameter which affects our noisy measurement?

Given the on and off rates for the receptors (measured in single molecule measurements), we can calculate the mutual information contained in one measurement snapshot

result in bits for small gradients

6Microfluidics

Revolutionizing measurementsSoft lithographyStable gradientsControlled geometriesRapid switching

Brings experiments to where they can be compared more quantitatively to theory

From A. Groisman lab; Skoge et al (2010)7Cell migration in a gradient

cAMP gradient

flow rate 640 m/s

1h real time = 8 sec movieFrom Songet al8tD = l2/D

D= (kT)/(6ha)a: size of theparticleh: viscocity of the fluidT: absolute tempa ~ (MW)1/3

Re=rul/h At low Re, viscous drag dominates.u: fluid flow speed,L: length scale (channl diameter)r: densityh: viscocity

Laminar flow is smooth predictable flow which always occurs at Re