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Many hands make light work: How cells use tiny forces to shape big tissues Steve Del Signore QB Bootcamp 1/12/2017 http://www.dailymail.co.uk/news/article-2603204

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Page 1: Many hands make light work: How cells use tiny forces to

Many hands make light work:

How cells use tiny forces to shape big tissues

Steve Del SignoreQB Bootcamp

1/12/2017

http://www.dailymail.co.uk/news/article-2603204

Page 2: Many hands make light work: How cells use tiny forces to

How do we get assembled?

Page 3: Many hands make light work: How cells use tiny forces to

Nature Methods 9:755 (2012)

Diverse tissue dynamics shape the developing embryo

Page 4: Many hands make light work: How cells use tiny forces to

Gene expression Nat Rev Gen 10:517

Cell Shape Proliferation

Mechanical inputs can modulate diverse cell behaviors

Page 5: Many hands make light work: How cells use tiny forces to

Nat Rev MCB 25:647 (2014)Cancer Cell 8:241 (2005)

Basement membrane Cell contacts Nuclei

Matrix stiffness

Normal Cancer

Mechanical inputs can drive pathological cell behaviors

Page 6: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale processSp

ace

Timeshort(ms)

Interminable(mins-hrs)

tiny(nm)

huge(mm)

Big picture message:

Normal development depends on real physical mechanisms that mediate interaction among these space and time scales

Part I: The playersPart II: The game

Page 7: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale processSp

ace

Timeshort(ms)

Interminable(mins-hrs)

tiny(nm)

huge(mm)

What tissue movements promote development?What cell behaviors drive tissue dynamics?What are the molecular forces that underliecell behavior?

Part I: The players

Page 8: Many hands make light work: How cells use tiny forces to

What tissue behaviors sculpt the developing organism?

Bending

Growth (+/-)

Shape change/elongation

Page 9: Many hands make light work: How cells use tiny forces to

Nat Cell Bio 17:1247 (2015)

Tissue elongation: Drosophila germband extension

Page 10: Many hands make light work: How cells use tiny forces to

Patterned proliferation or death

Cell shape change

Reorganization or migration

What cell behaviors drive tissue morphogenesis?

Page 11: Many hands make light work: How cells use tiny forces to

Nature 429:667

Cell reorganization drives germband extension: Single cell contact remodeling

Page 12: Many hands make light work: How cells use tiny forces to

Dev Cell 11:459

Cell reorganization drives germband extension: Multicellular contact remodeling

Page 13: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale processSp

ace

Timeshort(ms)

Interminable(mins-hrs)

tiny(nm)

huge(mm)

What tissue movements promote development?What cell behaviors drive tissue dynamics?What are the molecular forces that underliecell behavior?

Part I: The playersElongation

Rearrangement

Page 14: Many hands make light work: How cells use tiny forces to

Cell adhesion and actomyosin tension drive cell dynamics

F-actin

Myosin minifilament

Adhesion complex

Page 15: Many hands make light work: How cells use tiny forces to

J Exp Zoo. 128:53 (1955)

Nature 431:647 (2004)

?

Adhesion originally considered dominant force

Page 16: Many hands make light work: How cells use tiny forces to

Nature Cell Biol 10:429 (2008)

A B C A C B

Adhesion Tension

Quantification of adhesion and cortical tension in cells

Page 17: Many hands make light work: How cells use tiny forces to

Does surface tension or adhesion predict sorting behavior?

Adhesion

SurfaceTension

A+C A+B C+B

C>B>A

A>C>B

Nature Cell Biol 10:429 (2008)

Page 18: Many hands make light work: How cells use tiny forces to

Surface tension predicts sorting; adhesion does not

Nature Cell Biol 10:429 (2008)

Adhesion

SurfaceTension

A+C A+B C+B

C>B>A

A>C>B

Page 19: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale processSp

ace

Timeshort(ms)

Interminable(mins-hrs)

tiny(nm)

huge(mm)

What tissue movements promote development?What cell behaviors drive tissue dynamics?What are the molecular forces that underliecell behavior?

Part I: The playersElongation

Rearrangement

(mainly) Tension

Page 20: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale processSp

ace

Timeshort(ms)

Interminable(mins-hrs)

tiny(nm)

huge(mm)

How are forces controlled in space and time?How are forces integrated across the tissue?

Part II: The gameElongation

Rearrangement

(Mainly) tension

Page 21: Many hands make light work: How cells use tiny forces to

Cells can systematically polarize

Polarity gene mutantControl

Development 134:647 (2007)

Page 22: Many hands make light work: How cells use tiny forces to

Dev Cell 11:459 2006Dev Cell 17:736 (2009)

Contractile Adhesive

Adhesion and contractile proteins polarize during cell intercalation

Page 23: Many hands make light work: How cells use tiny forces to

Contractile proteins increase tension on vertical junctions

ev Cell 17:736 (2009)D

Page 24: Many hands make light work: How cells use tiny forces to

Tension itself enhances recruitment of Myosin!

Dev Cell 17:736 (2009)

Myosin recruitment

Page 25: Many hands make light work: How cells use tiny forces to

Molecules and forces are polarized within the cellTissue level polarity cues and local forces both organize

Suggests model in which stable tension biases rearrangementsto favor vertical intercalation and horizontal elongation

Molecules and forces are organized across subcellular & multicellular domains

Page 26: Many hands make light work: How cells use tiny forces to

F-actin Myosin

Nature 468:1110

Actomyosin exhibits pulsed flow at the surface of remodeling cells

Page 27: Many hands make light work: How cells use tiny forces to

Nature 468:1110

Cell surface actomyosin correlates with junction shrinking

Page 28: Many hands make light work: How cells use tiny forces to

Laser ablation of surface myosin reverses junction constriction

Page 29: Many hands make light work: How cells use tiny forces to

Gastrulation/EMT

Cell migration

COGD 21:671 (2011)Nature 457:495 (2009)

Dorsal closure/ “wound healing”

Cell 137:1331 (2009)

Pulsed cell and molecular dynamics are everywhere!

Page 30: Many hands make light work: How cells use tiny forces to

JCB 206:435 (2014)

Blocking pulsed constriction disrupts cell & tissue dynamics

Page 31: Many hands make light work: How cells use tiny forces to

Why are pulsed dynamics so important?

Integrate time scales‘Sample’ energy states?Allow for more dynamic/robust regulation?Coordination of cell behavior

Page 32: Many hands make light work: How cells use tiny forces to

Morphogenesis is a multiscale problem

Space

Tim

e

fast(ms)

interminable(tens min)

tiny(nm)

huge(mm)

What are the forces that deform cells?What controls these forces in space and time?How are forces integrated across the tissue?

Page 33: Many hands make light work: How cells use tiny forces to

F-actin

Myosin minifilament

Adhesion complex

No (epithelial) cell is an island

Page 34: Many hands make light work: How cells use tiny forces to

Nat Cell Bio 17:1247 (2015)

Junction expansion requires help from neighbors

Page 35: Many hands make light work: How cells use tiny forces to

Myosin II::GFP

Top

-bo

tto

mcu

ttin

g

Left

-rig

ht

cutt

ing

Nat Cell Bio 17:1247 (2015)

Junction expansion requires constriction in left-right neighbors

Page 36: Many hands make light work: How cells use tiny forces to

eLife 2016;5:e10757

Constriction in neighboring cells is sufficient to induce contact remodeling

Page 37: Many hands make light work: How cells use tiny forces to

We can do more biggerer

http://www.gofigure2.org/

Development 2014 141: 2895

Elife 2016:e14334

Page 38: Many hands make light work: How cells use tiny forces to

Cell 142:773 (2010)

Hinge Wing

Mechanical interactions between tissues regulate cell polarity and intercalation

Page 39: Many hands make light work: How cells use tiny forces to

Cell 142:773 (2010)C

ell b

on

d t

ensi

on

Bond angle:

15 hours17 hours23 hours26 hours

Cell junction tension suggests hinge pulls on wing

Page 40: Many hands make light work: How cells use tiny forces to

Cell 142:773 (2010)

Blocking tension input prevents tissue polarization, cell flow, and elongation

Page 41: Many hands make light work: How cells use tiny forces to

Cell 142:773 (2010)

Tension and cell flow reorganize the wing during elongation

Page 42: Many hands make light work: How cells use tiny forces to

Trying to put it all together…

Page 43: Many hands make light work: How cells use tiny forces to

Which are the initiating events? What mechanisms control pulsed forces?How do other mechanical properties such as stiffness or protrusion contribute? Lots of positive feedback mechanisms, but how do these pathways get attenuated?

Some unanswered questions

Page 44: Many hands make light work: How cells use tiny forces to

QB ProgramJane KondevAvi RodalRodal Lab

Acknowledgements


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