Cooperating morphogens control hoxd gene expression in the developing vertebrate limb.

A mechanism was recently proposed which controls the expression of Hoxa genes in the developing vertebrate limb. This is a three-dimensional diffusion model of a morphogen Ma secreted at the apical ectodermal ridge. The morphogen Ma is at the same time degraded by first order chemical kinetics. The emerging diffusion gradient, supplemented with a natural sequence of thresholds, can explain the spatial and temporal collinearities of the Hoxa gene expression domains. In the present model it is assumed that a second diffusing morphogen Mz is produced at the zone of polarizing activity. A concentration superposition of morphogens Ma and Mz can then explain the observed pattern of expression of Hoxd-10, 11, 12, and 13 during normal limb development (spatial and temporal collinearity). The associated thresholds for gene expression increase sequentially from Hoxd-10 to Hoxd-13 (threshold collinearity). The observed deformations or deletions of these expression domains in manipulated limbs are also explained by the model. Additional model predictions are proposed to test the validity of the model. In patterning two mechanisms are mainly considered as responsible for signalling: (i) a gradient of a long-range morphogen created by passive diffusion; and (ii) a short-range inducer initiating a cascade of consecutive signals. A time-test is proposed which distinguishes the modes of specific gene expressions for these distinct signalling mechanisms.