(352a) Modeling the Molecular Crosstalk Between a Growth Factor and a Differentiation Inducing Receptor

The Interleukin-7 receptor (IL-7R) and the precursor to the B cell antigen receptor (pre-BCR) function to regulate the balance between pre-B cell proliferation and their differentiation. The former signaling system promotes cell survival and proliferation whereas the latter stimulates antibody light chain gene rearrangement thereby enabling the generation of mature B-lymphocytes. The architecture of the gene regulatory network (GRN) orchestrating the interplay between the two signaling systems has been recently elucidated [1].

IL-7 signaling is coupled to STAT5, PI3K and Akt to promote cell proliferation. On the other hand, pre-BCR signaling is coupled to Syk, BLNK, FoxO1 and Pax5, which induce cellular differentiation. Weakening of IL-7R signaling, or an alteration in pre-BCR signaling, results in cell-cycle arrest and cell differentiation [1].

The complexity level of this GRN is high. Therefore, guided by experimental observations, we are developing a mathematical model to fully grasp the multifaceted network underlying the crosstalk between IL-7R and pre-BCR. It appears that this GRN shares a key characteristic with previously studied systems [2,3]. This characteristic refers to the mutual (and sometimes indirect) repression between two primary modules, FoxO1-Pax5 and IL-7R, and gives rise to bistable behavior when described by non-linear dynamics. Interestingly, preliminary results indicate that the architecture of the presented GRN does generate bistability under certain parameters. The two stable steady states, namely cell proliferation and differentiation, are separated by unstable steady states. As discussed previously [3], these unstable steady states cannot be observed experimentally and can only be explored mathematically.

Our mathematical framework investigates all the possible states of the IL-7/pre-BCR GRN. Sensitivity analysis with respect to IL-7 concentration allows for defining its threshold for flipping this molecular circuit (from cell differentiation to proliferation and vise versa) and the parameters that govern it. Our computational predictions will be validated against experimental measurements aiming to thoroughly explain the dynamics dictating whether cells undergo differentiation or proliferation.

1)   K. Ochiai, M. Maienschein-Cline, M. Mandal, J.R. Triggs, E. Bertolino, R. Sciammas, A.R. Dinner, M.R. Clark, and H. Singh, Nature Immunology, 13(3):300-307, 2012.

2)   P. Laslo, C.J. Spooner, A. Warmash, D.W. Lancki, H.J. Lee, R. Sciammas, B.N. Gantner, A.R. Dinner,and H. Singh, Cell, 126(4):755-766, 2006.

3)   D. Muzzey and A. van Oudenaarden, Cell, 126(4):650-652, 2006.