Rethinking positional information and digit identity: The role of late interdigit signaling

Abstract

Seminal work from John Fallon's lab has illuminated how digit identity determination involves ongoing late regulation and occurs progressively during phalanx formation. Complementary genetic analyses in mice and several papers in this special issue have begun to flesh out how interdigit signaling accomplishes this, but major questions remain unaddressed, including how uncommitted progenitors from which phalanges arise are maintained, and what factors set limits on digit extension and phalanx number, particularly in mammals. This review summarizes what has been learned in the two decades since control of digit identity by late interdigit signals was first identified and what remains poorly understood, and will hopefully spark renewed interest in a process that is critical to evolutionary limb adaptations but nevertheless remains enigmatic.

Sonic Hedgehog is not a limb morphogen but acts as a trigger to specify all digits

“…Digit identity is morphologic in nature, arising via distinct organizations of the same tissues and not based in cell fate changes, features suggesting progressive specification. Indeed, work in both chick and mouse indicates that late interdigit signaling centers 34, 44–47 impinge on digit tip progenitors to regulate phalanx numbers formed, determining final digit identities. Shh may regulate digits specified at particular A-P limb positions via relay signals to establish such late signaling centers (Fig.…”

Sonic hedgehog is not a limb morphogen but acts as a trigger to specify all digits in mice

“…Digit identity is morphologic in nature, arising via distinct organizations of the same tissues and not based in cell fate changes, features suggesting progressive specification. Indeed, work in both chick and mouse indicates that late interdigit signaling centers impinge on digit-tip progenitors to regulate phalanx numbers formed, determining final digit identities (Dahn and Fallon, 2000;Huang and Mackem, 2021;Huang et al, 2016;Suzuki et al, 2008;Witte et al, 2010). Shh may regulate digits specified at particular A-P limb positions via relay signals to establish such late signaling centers (Figure 6E).…”

Self-organized BMP signaling dynamics underlie the development and evolution of tetrapod digit patterns

“…Digits are segmented into individual digit bones, termed phalanges, which are connected to each other by synovial joints that facilitate relative motion of adjacent bones and, thus, digit flexion. Thanks to this modular architecture, highly distinct digit patterns have evolved to enable locomotory behaviors as diverse as walking, swimming, flying, or the execution of fine motor skills (4). These patterns are individualized both in terms of number and size of their phalangeal bones and can vary across species as well as within the same limb.…”

“…These patterns are individualized both in terms of number and size of their phalangeal bones and can vary across species as well as within the same limb. For the latter, differences in phalangeal formulas are a manifestation of distinct digit identities along the anteroposterior axis of the distal limb domain, the so-called autopod (4, 5).…”