The developing limb has been a very influential system for studying pattern formation in vertebrates. In the past, classical embryological models have explained how patterned structures are generated along the two principal axes of the limb: the proximodistal (shoulder to finger) and anteroposterior (thumb to little finger) axes. Over time, the genetic and molecular attributes of these patterning models have been discovered, while the role of growth in the patterning process has been only recently highlighted. In this review, we discuss these recent findings and propose how the various models of limb patterning can be reconciled.
IntroductionThe developing limb has long been a pioneering model for understanding pattern formation: the process in which the spatial organisation of differentiated cells and tissues is generated in the embryo. One aspect of limb development that has perplexed several generations of researchers is the importance of growth. This might appear to be a trivial problem because growth occurs throughout the period when pattern is laid down and so, in the broadest sense, it is obviously required for development. However, controversy surrounds whether growth is required for the actual specification of pattern.Pattern formation can be considered as a two-step process; first cells are informed of their position and, thus, acquire a positional value (specification); cells then remember and interpret this value to form the appropriate structures (differentiation) (Wolpert, 1969). In the developing chick leg, specification cues can be experimentally overridden until quite a late stage, leading to altered differentiation and morphogenesis, thus revealing remarkable developmental plasticity (Dahn and Fallon, 2000). Three main scenarios for the role of growth in pattern formation have been suggested and can be illustrated by the classical French flag model (Wolpert, 1969;Wolpert, 1989). In one scenario, growth itself is proposed to specify positional values directly (Fig. 1A). In another, local growth generates positional values by intercalating existing disparate positional values, as seen in regenerating amphibian limbs (French et al., 1976) (Fig. 1B). In the third scenario, growth is proposed to play no direct patterning role, but simply to expand positional values that have already been specified by a different mechanism, such as a concentration gradient of a long-range morphogen (Fig. 1C).Studies of the genetic basis of some human congenital limb defects, such as Apert syndrome (Wilkie et al., 1995) and preaxial polydactyly (PPD) (Lettice et al., 2002) have complemented experimental findings in the main model organisms, the chick and the mouse. However, in order to understand the relationship between genotype and phenotype, we need to have a better grasp of the basic patterning mechanisms that operate during limb development, knowledge that could be incorporated into our current models of embryonic pattern formation. Thus, it is encouraging that several recent papers on limb development propose pa...