THIRTY-FIVE Positional Information and Pattern Formation

The concept of positional information proposes that cells acquire positional values as in a coordinate system, which they interpret by developing in particular ways to give rise to spatial patterns. Some of the best evidence for positional information comes from regeneration experiments, and the patterning of the leg and antenna in Drosophila, and the vertebrate limb. Central problems are how positional information is set up, how it is recorded, and then how it is interpreted by the cells. A number of models have been proposed for the setting up of positional gradients, and most are based on diffusion of a morphogen and its interactions with extracellular molecules; however, diffusion may not be reliable mechanism. There are also mechanisms based on timing. There is no good evidence for the quantitative aspects of any of the proposed gradients and details how they are set up. The way in which a signaling gradient regulates differential gene expression in a concentration-dependent manner also raises several technical and quite difficult issues. A key feature of positional information being the basis for pattern formation is that there is no prepattern in the embryo. Positional information is a concept that relates to pattern formation, that is, the development of spatial organization in the embryo that results from cells differentiating at specific positions. The concept of positional information proposes that cells acquire positional identities as in a coordinate system, and then interpret their positions to give rise to spatial patterns (Wolpert, 2011). It had its origin over 100 years ago, when Hans Driesch was working on sea urchin development. He found that if he separated the cells of the embryo at the two-cell stage, each developed into a small but normal larva. This implies that their patterning involves a mechanism for whose pattern is size invariant. He also claimed—mistakenly—that if any region of the early embryo were removed, the embryo still developed normally. He, therefore, Current Topics in Developmental Biology, Volume 117 # 2016 Elsevier Inc. ISSN 0070-2153 All rights reserved. http://dx.doi. org/10.1016/bs.ctdb. 2015.11. 008 597 concluded that there was a coordinate system that specified the position of each cell so that it could develop in the correctmanner, but this was amystical process. He was of course wrong, but his ideas helped give rise to the French flag mechanism for patterning, the pattern of flags being the same no matter their size (Wolpert, 1969). This is the basis of positional information which requires that the cells have positional values as in a coordinate system. However, few models take change of size into account as there is a scaling effect, which most models of morphogens do not take into account. There are several proposed mechanisms such as two diffusible molecules that emanate from opposing poles and define the activation profile through their ratio. A model based on expansion–repression by Ben-Zvi and Barkai (2010) suggests that scaling emerges as a natural consequence of a feedback topology. Positional information implies that cells have a graded set of values that varies continuously along an axis, and under the influence of the local positional information, a cell obtains a positional value which they interpret their position by developing in particular ways. One of the mainmechanisms proposed for setting up positional information is based on gradients of morphogens which are diffusible molecules produced by the cells, whose concentration specifies position. This was first proposed by Crick (1970) because the lengths of the proposed gradients, such as those in the vertebrate limb and insect imaginal discs, are quite small, around 50 cells long (Wolpert, 1969). The mechanisms for specifying position are discussed later. Quite simple experiments that show that cells have positional values came from regeneration experiments that show intercalation of missing regions of invertebrate limbs (French, Bryant, & Bryant, 1976). There seems to be a set of positional values along the tibia of the cockroach leg since if a portion of the tibia is removed, the missing region will be replaced by intercalary regeneration. More striking, when a proximal cut tibia is grafted on to a more distal site making the tibia longer, intercalation makes the tibia even longer by intercalating the missing positional values. Another clear example of intercalation is from the salamander limb, when a distal regeneration blastema is grafted in place of a proximal one, and the missing regions are intercalated to form a normal limb. An important example providing evidence for positional information came from the antenna and leg ofDrosophila. If the Hox gene Antennapedia, which is normally expressed in parasegments 4 and 5 of the Drosophila embryo, is expressed in the head region, the antenna develops as a leg. Clones of Antennapedia cells in the antenna disc develop as leg cells, and the type of developed leg cells depends on their position along the proximodistal axis; if, for example, they are at the tip, they will develop 598 Lewis Wolpert