Modeling signaling and migration of the Posterior Lateral Line primordium with agent based models Formation of the Posterior Lateral Line (PLL) is spearheaded by the PLL primordium (PLLp), a collection of about 100 cells that migrates from the ear to the tip of the tail periodically depositing sensory organs called neuromasts from its trailing end. Previous studies have provided a remarkable framework for understanding how chemokine signaling steers the PLLP and how juxtaposed mutually inhibitory Wnt and FGF signaling systems coordinate cell fate and morphogenesis of proto-neuromasts in the PLLp. An attempt to recapitulate the self-organization of the PLLp using Netlogo, an agent based modeling platform, showed that while the current framework helps account for many of the emergent properties of this system a number of questions remain unanswered. Further development of the computational model has provided potential answers to some of these questions that are now being experimentally tested. We have shown how a Wnt-FGF signaling based reaction diffusion system can account for periodic establishment of center restricted FGF signaling centers, within which central hair cell progenitors can be specified by lateral inhibition. We have also shown how systematic changes in the strength of Wnt and FGF signaling could account for spontaneous emergence of center restricted Wnt signaling centers at the trailing end of the PLLp, a phenonomena that we had observed but could not previously easily explain. Another mechanical agent based model of the PLLp based on our current understanding shows how polarized expression of chemokine receptors, CXCR4b in leading cells and CXCR7b in trailing cells, allows the PLLp to migrate effectively along a relatively uniform stripe of chemokine expression from the ear to the tip of the tail. In this model, CXCR4b cells at the leading edge respond with protrusive activity in the direction they encounter higher than threshold levels of the chemokine, Sdf1. On the other hand CXCR7b expressing cells do not respond to Sdf1 with protrusive activity. However, both receptors have the ability to interact with, internalize and degrade Sdf1. Cells are held together by visco-elastic links. Our model suggests that while degradation of chemokines by trailing CXCR7b expressing cells is not essential for effective migration, inability of these cells to respond to Sdf1 with protrusive activity is. Similations using this model revealed phenonomena could not be duplicated and helped identify specific deficits in our original model. We have now found that an additional mechanism allows trailing cells to follow leading cells and helps account for a broader spectrum of PLLp cell behavior. The balance of Wnt/FGF signaling and factors that influence incorporation of cells into neuromasts regulate the frequency of lateral line neuromast formation and deposition. The posterior lateral line primordium (PLLp) migrates from the ear to the tip of the tail periodically depositing neuromasts, however, mechanisms that determine their deposition rate remain poorly understood. Neuromasts are deposited more frequently and the PLLp system terminates prematurely in lef1-deficient embryos. It was suggested that this results from either reduced proliferation in the leading domain of the PLLp or premature differentiation of progenitors. We found that knockdown of another facilitator the Wnt signaling pathway, rspo3, reduces proliferation in a manner similar to knockdown of lef1. However, it does not accelerate neuromast deposition or cause premature termination of the PLLp, suggesting that these changes in lef1 deficient embryos may not be linked to changes in proliferation. Instead, we found that they are related to a role of lef1 in determining expression of the FGF signaling inhibitor, Dusp6. Wnt signaling locally inhibits FGF signaling, and FGFs expressed in response to Wnt-signaling first initiate FGF signaling and proto-neuromast formation at the trailing end of the PLLp. FGF signaling inhibits Wnt signaling and periodic formation of proto-neuromasts is accompanied by progressive restriction of Wnt signaling to a smaller leading domain of the PLLp. We found that, in the context of the tug-of-war between Wnt and FGF signaling, reducing FGF signaling delays formation and deposition of the first neuromast. On the other hand, loss of Wnt mediator lef1, accelerates neuromast formation, the deposition rate and the termination of the PLLp system, as loss of lef1-dependent Dusp6 expression facilitates incorporation of cells into proto-neuromasts and their deposition as neuromasts.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2012
Total Cost
$1,235,365
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