Navigating Biochemical Pathways for Cell Polarization and Motility (A Personal Journey)
Presenter
January 11, 2017
Abstract
Many cell types, including cells of the immune system, are able to polarize and crawl in response to chemical or mechanical stimuli. In this way, they can perform vital functions such as immune surveillance, wound healing, and tissue development. I will describe our efforts to understand the underlying biochemistry governing the initial direction sensing, polarization, cell shape change, and motility. While much of the biology is undergoing rapid discovery, we have found that mathematical ideas supply additional tools. Such tools help to decipher underlying mechanism, to weed between competing hypotheses, and to suggest new experimental tests. On the same journey, we also encountered some new and interesting mathematics.
Supplementary Materials
Timecodes
- 01:05
- Navigating Biochemical Pathways for Cell Polarization and Motility
- 01:05
- Navigating Biochemical Pathways for Cell Polarization and Motility
- 01:20
- Important People
- 01:20
- Important People
- 02:36
- Hans Meinhardt & Lee A Segel
- 02:36
- Hans Meinhardt & Lee A Segel
- 03:03
- Chemotaxis
- 03:03
- Chemotaxis
- 03:31
- Reaction-Diffusion Equation
- 03:31
- Reaction-Diffusion Equation
- 04:00
- Fisher's RD Equation
- 04:00
- Fisher's RD Equation
- 04:29
- Bistable RD Equation
- 04:29
- Bistable RD Equation
- 04:56
- Traveling Wave Solution
- 04:56
- Traveling Wave Solution
- 05:21
- Pattern Formation (in RD Sys)
- 05:21
- Pattern Formation (in RD Sys)
- 06:18
- Pretty Pattern
- 06:18
- Pretty Pattern
- 06:39
- Simple Pattern
- 06:39
- Simple Pattern
- 06:57
- What is the biological problem and why it is important
- 06:57
- What is the biological problem and why it is important
- 07:09
- Neutrophil Chasing Bacterium
- 07:09
- Neutrophil Chasing Bacterium
- 08:11
- Step 1: Cell Polarization
- 08:11
- Step 1: Cell Polarization
- 08:40
- Cell Polarization Model (1974)
- 08:40
- Cell Polarization Model (1974)
- 09:09
- Step 2: Cell Motility
- 09:09
- Step 2: Cell Motility
- 09:26
- Cell Motility
- 09:26
- Cell Motility
- 09:40
- Cell Motility (cont.)
- 09:40
- Cell Motility (cont.)
- 10:18
- Cell Motility
- 10:18
- Cell Motility
- 10:38
- Actin at the Front Edge
- 10:38
- Actin at the Front Edge
- 11:04
- Models for Actin-Powered Cell
- 11:04
- Models for Actin-Powered Cell
- 12:00
- Cell Polarization Proteins
- 12:00
- Cell Polarization Proteins
- 12:25
- Cell Polarization Proteins
- 12:25
- Cell Polarization Proteins
- 12:49
- Cell Polarization
- 12:49
- Cell Polarization
- 13:25
- Question Break
- 13:25
- Question Break
- 13:41
- Question: Is actin based motility is really unique or are there other cell that can move in other ways as well?
- 13:41
- Question: Is actin based motility is really unique or are there other cell that can move in other ways as well?
- 14:45
- Important Pattern: Cell Polarization
- 14:45
- Important Pattern: Cell Polarization
- 15:16
- What properties of these Small GTPases lead to their chemical polarization?
- 15:16
- What properties of these Small GTPases lead to their chemical polarization?
- 15:32
- Simplified Geometry
- 15:32
- Simplified Geometry
- 16:00
- How can we explain GTPase pattern formation in ID (across cell diameter)?
- 16:00
- How can we explain GTPase pattern formation in ID (across cell diameter)?
- 16:38
- Rho GTPasses: Crosstalk
- 16:38
- Rho GTPasses: Crosstalk
- 17:19
- Traveling Waves, but not Robust Polarization
- 17:19
- Traveling Waves, but not Robust Polarization
- 17:49
- Small GTPases: Cycling
- 17:49
- Small GTPases: Cycling
- 18:14
- Active Forms Bind to Membrane
- 18:14
- Active Forms Bind to Membrane
- 18:45
- Include Inactive Forms of GTPases
- 18:45
- Include Inactive Forms of GTPases
- 19:10
- Wave Stalls to Form Polarized Cell
- 19:10
- Wave Stalls to Form Polarized Cell
- 19:27
- Initial Stimulus
- 19:27
- Initial Stimulus
- 19:42
- Final Robust Polarization
- 19:42
- Final Robust Polarization
- 19:58
- GTPases Signaling to Actin
- 19:58
- GTPases Signaling to Actin
- 20:27
- Cell Shape Sequence
- 20:27
- Cell Shape Sequence
- 20:47
- Additional Layers
- 20:47
- Additional Layers
- 21:06
- Rac and Rho
- 21:06
- Rac and Rho
- 21:31
- What makes this happen?
- 21:31
- What makes this happen?
- 22:00
- Caricature
- 22:00
- Caricature
- 22:39
- Positive Feedback
- 22:39
- Positive Feedback
- 23:03
- 100-1000 Fold Difference in Rate of Diffusion
- 23:03
- 100-1000 Fold Difference in Rate of Diffusion
- 23:21
- Simplified Geometry
- 23:21
- Simplified Geometry
- 23:55
- RD Model
- 23:55
- RD Model
- 24:25
- Rescaled (There is a Small Parameter)
- 24:25
- Rescaled (There is a Small Parameter)
- 24:53
- Stimulus Initiates Wave
- 24:53
- Stimulus Initiates Wave
- 25:22
- Using Up Inactive Form
- 25:22
- Using Up Inactive Form
- 25:24
- Wave Stalls by Substrate Depletion
- 25:24
- Wave Stalls by Substrate Depletion
- 25:36
- Comparison
- 25:36
- Comparison
- 26:04
- Comparison
- 26:04
- Comparison
- 26:32
- Bifurcation Analysis
- 26:32
- Bifurcation Analysis
- 27:32
- GTPase Cycling
- 27:32
- GTPase Cycling
- 28:02
- Question Break
- 28:02
- Question Break
- 28:10
- Question: Do you need non-linear kinetics to obtain robust polarization?
- 28:10
- Question: Do you need non-linear kinetics to obtain robust polarization?
- 29:05
- More Recent: Shortcuts to Analysis
- 29:05
- More Recent: Shortcuts to Analysis
- 30:38
- Local Perturbation Analysis
- 30:38
- Local Perturbation Analysis
- 31:33
- Basal Activation Rate Diagram
- 31:33
- Basal Activation Rate Diagram
- 31:45
- Basal Activation Rate Diagram (cont.)
- 31:45
- Basal Activation Rate Diagram (cont.)
- 32:17
- New Regime Discovered
- 32:17
- New Regime Discovered
- 33:03
- Initial Conditions
- 33:03
- Initial Conditions
- 33:28
- Evolve Differently
- 33:28
- Evolve Differently
- 33:32
- Three Coexisting Spatial SS
- 33:32
- Three Coexisting Spatial SS
- 33:54
- Connection with Experiments
- 33:54
- Connection with Experiments
- 33:59
- Rae Activation Drives Cell Polarity
- 33:59
- Rae Activation Drives Cell Polarity
- 34:50
- Experiment and Model
- 34:50
- Experiment and Model
- 35:26
- Cell Response
- 35:26
- Cell Response
- 35:51
- Model and Experiment
- 35:51
- Model and Experiment
- 36:37
- Single Cell Wound Healing
- 36:37
- Single Cell Wound Healing
- 37:22
- Reconstruct Details of Signaling Network
- 37:22
- Reconstruct Details of Signaling Network
- 37:45
- Expts Model
- 37:45
- Expts Model
- 38:21
- Model Accounts for Expt Data
- 38:21
- Model Accounts for Expt Data
- 38:50
- Melanoma Cell Motility
- 38:50
- Melanoma Cell Motility
- 39:52
- Orientation Angle
- 39:52
- Orientation Angle
- 40:09
- Rac and Rho
- 40:09
- Rac and Rho
- 40:44
- ECM-Cell Contact and Feedback
- 40:44
- ECM-Cell Contact and Feedback
- 41:50
- ECM-Cell Contact and Feedback (cont.)
- 41:50
- ECM-Cell Contact and Feedback (cont.)
- 42:02
- Competition of Two Lamellipods
- 42:02
- Competition of Two Lamellipods
- 42:10
- ... With Signaling in Each One
- 42:10
- ... With Signaling in Each One
- 42:18
- ... Causing Cycles of Expansion/Contraction
- 42:18
- ... Causing Cycles of Expansion/Contraction
- 42:28
- ... First in One Lamellipod then in the Other
- 42:28
- ... First in One Lamellipod then in the Other
- 42:37
- Model Explains Cell Behaviors
- 42:37
- Model Explains Cell Behaviors
- 43:01
- Future Perspectives
- 43:01
- Future Perspectives
- 43:31
- Conclusions
- 43:31
- Conclusions
- 44:08
- Thanks
- 44:08
- Thanks
- 44:46
- Question: Would it be feasible to use Eric Betzig's super resolved fluorescent microscopy to show actual actin-myosin polarization rates to establish parameter values for this model?
- 44:46
- Question: Would it be feasible to use Eric Betzig's super resolved fluorescent microscopy to show actual actin-myosin polarization rates to establish parameter values for this model?
- 46:09
- Question: Is cell polarization truly unidirectional or is it possible that there are stochastic bidirectional events occurring as well?
- 46:09
- Question: Is cell polarization truly unidirectional or is it possible that there are stochastic bidirectional events occurring as well?