Fig. 3.

Hypothetical model of SHH signaling and growth. SHH concentration gradient in the midface modeled as L(x)=L·exp(–x/C) where L is the ligand concentration and C is the decay coefficient (Eldar et al., 2003). Downstream targets of the pathway, such as those promoting cell cycle acceleration, are hypothesized to be rapidly activated at L_shh (e.g. Lai et al., 2004), and D_n(L) is the linear distance from the ligand signaling source where L_n>L_shh. The volume of cells (V_n) where L_n>L_shh for any D_n is approximately equal to 4/6·π·D ³_n (i.e. half the volume of a sphere with radius D_n). This model predicts that mutations affect growth by altering either (1) ligand concentration (L) or decay (C), or (2) the sensitivity of cells to ligand concentration (i.e. L_shh), and linear changes in concentration result in nonuniform responses. Not shown in this figure is that the FEZ may be inhibited in the midline above a crucial concentration of SHH in the brain, thereby limiting the maximal effective FEZ size and lateralizing growth zones.