Limits...
A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.


B-cell decision enforcement is NF-κB cRel dependentA–H Time-lapse microscopy images of wild-type B cells stimulated with 250 nM CpG (A, B), NF-κB cRel-deficient B cells stimulated with 250 nM CpG (C, D), wild-type cells stimulated with 10 nM CpG (E, F), and wild-type B cells stimulated with 250 nM CpG and pretreated with 1 ng/ml rapamycin for 1 h (G, H) were tracked. The observed cumulative distributions (A, C, E, G) for time to start growing (Tgro), time to divide (Tdiv), and time to die (Tdie) were used to estimate the minimum probability of observing grown cells that die in generation 0 assuming that division and death were occurring simultaneously (molecular race), and compared to the actual sampled probabilities for each condition (B, D, F, H).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4358656&req=5

fig07: B-cell decision enforcement is NF-κB cRel dependentA–H Time-lapse microscopy images of wild-type B cells stimulated with 250 nM CpG (A, B), NF-κB cRel-deficient B cells stimulated with 250 nM CpG (C, D), wild-type cells stimulated with 10 nM CpG (E, F), and wild-type B cells stimulated with 250 nM CpG and pretreated with 1 ng/ml rapamycin for 1 h (G, H) were tracked. The observed cumulative distributions (A, C, E, G) for time to start growing (Tgro), time to divide (Tdiv), and time to die (Tdie) were used to estimate the minimum probability of observing grown cells that die in generation 0 assuming that division and death were occurring simultaneously (molecular race), and compared to the actual sampled probabilities for each condition (B, D, F, H).

Mentions: The model predictions regarding cRel's role in protecting growing cells from apoptosis (Fig6G), prompted us to examine our experimental data further. We tabulated the observed probability that a dying cell had grown for the wild-type, cRel-deficient, low stimulus, and rapamycin-treated conditions (Fig7). The probability of observing dying ‘growers’ approximately tripled when cells lacked cRel (Fig7D compare to B), suggesting that growth and death were no longer mutually exclusive. The increased probability was still lower than the minimum probability expected for a complete loss of decision enforcement, calculated using observed distributions for the time to start growing, divide, and die (Fig7C). A lack of decision enforcement was not seen when a lower dose of the stimulus (Fig7E and F) or rapamycin drug treatment (Fig7G and H) was used, confirming NF-κB cRel's specific role. These studies suggest that the phenomenological cell fate decision is mediated at the molecular level by cRel, which biases a cell fate race in growing cells against cell death, rendering them pre-determined for division.


A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

B-cell decision enforcement is NF-κB cRel dependentA–H Time-lapse microscopy images of wild-type B cells stimulated with 250 nM CpG (A, B), NF-κB cRel-deficient B cells stimulated with 250 nM CpG (C, D), wild-type cells stimulated with 10 nM CpG (E, F), and wild-type B cells stimulated with 250 nM CpG and pretreated with 1 ng/ml rapamycin for 1 h (G, H) were tracked. The observed cumulative distributions (A, C, E, G) for time to start growing (Tgro), time to divide (Tdiv), and time to die (Tdie) were used to estimate the minimum probability of observing grown cells that die in generation 0 assuming that division and death were occurring simultaneously (molecular race), and compared to the actual sampled probabilities for each condition (B, D, F, H).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358656&req=5

fig07: B-cell decision enforcement is NF-κB cRel dependentA–H Time-lapse microscopy images of wild-type B cells stimulated with 250 nM CpG (A, B), NF-κB cRel-deficient B cells stimulated with 250 nM CpG (C, D), wild-type cells stimulated with 10 nM CpG (E, F), and wild-type B cells stimulated with 250 nM CpG and pretreated with 1 ng/ml rapamycin for 1 h (G, H) were tracked. The observed cumulative distributions (A, C, E, G) for time to start growing (Tgro), time to divide (Tdiv), and time to die (Tdie) were used to estimate the minimum probability of observing grown cells that die in generation 0 assuming that division and death were occurring simultaneously (molecular race), and compared to the actual sampled probabilities for each condition (B, D, F, H).
Mentions: The model predictions regarding cRel's role in protecting growing cells from apoptosis (Fig6G), prompted us to examine our experimental data further. We tabulated the observed probability that a dying cell had grown for the wild-type, cRel-deficient, low stimulus, and rapamycin-treated conditions (Fig7). The probability of observing dying ‘growers’ approximately tripled when cells lacked cRel (Fig7D compare to B), suggesting that growth and death were no longer mutually exclusive. The increased probability was still lower than the minimum probability expected for a complete loss of decision enforcement, calculated using observed distributions for the time to start growing, divide, and die (Fig7C). A lack of decision enforcement was not seen when a lower dose of the stimulus (Fig7E and F) or rapamycin drug treatment (Fig7G and H) was used, confirming NF-κB cRel's specific role. These studies suggest that the phenomenological cell fate decision is mediated at the molecular level by cRel, which biases a cell fate race in growing cells against cell death, rendering them pre-determined for division.

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.