A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration.

Area of Science:

• Cell biology
• Developmental biology
• Biophysics

Background:

• Cell migration is guided by chemoattractant gradients.
• Optimal directional signaling occurs when attractant concentrations approximate the receptor's dissociation constant (K_d).
• It remains unknown if this principle applies to in vivo cell migration.

Purpose of the Study:

• To investigate if the zebrafish posterior lateral line primordium buffers its chemoattractant (Cxcl12) to maintain concentrations near its receptor's (Cxcr4) K_d for robust migration.
• To determine the role of the Cxcl12/Cxcr4 axis and its associated negative-feedback loop in regulating directional cell movement.

Main Methods:

• Quantitative analysis of Cxcl12 gradient concentrations and Cxcr4 K_d in migrating zebrafish primordia.
• Experimental manipulation of Cxcr4 K_d and the Ackr3-mediated negative-feedback loop.
• Assessment of primordium migration directionality.
• Quantitative modeling of the observed mechanisms.

Main Results:

• The Cxcl12 gradient in zebrafish primordium migration ranged from 0 to 12 nM, closely matching the Cxcr4 K_d of 3.4 nM.
• Increasing the Cxcr4 K_d impaired primordium migration directionality.
• Disrupting the negative-feedback loop involving Cxcl12 and its clearance receptor Ackr3 also reduced migration directionality.
• Buffering of Cxcl12 levels by Ackr3 is crucial for maintaining optimal concentrations for directed migration.

Conclusions:

• Directed cell migration, exemplified by the zebrafish posterior lateral line primordium, depends on a precise alignment between chemoattractant concentration and receptor binding affinity.
• A negative-feedback mechanism involving Cxcl12 and Ackr3 actively buffers chemokine levels to maintain this critical concentration range.
• This buffering mechanism ensures robust and directional cell migration, suggesting it may be a general principle in biological systems.