An hypothesis: Phosphorylation fields as the source of positional information and cell differentiation—(cAMP, ATP) as the universal morphogenetic turing couple

Abstract

It is hypothesized that (cAMP, ATP) is the elusive, universal Turing morphogenetic couple, which defies the second law of thermodynamics, i.e. the inexorable march towards homogeneity. cAMP and ATP can be distributed nonhomogeneously because the whole of the intermediary metabolism is so organized that they mutually satisfy the Turing bifurcation conditions upon nonlocalized application of an extracellular ligand, in particular a soluble peptide growth factor, which is nature's distinguished universal bifurcation parameter, acting homogeneously in space and removing the substrate inhibition from adenylate cyclase and thus triggering embryonic induction by triggering the (cAMP, ATP) Turing system. The hypothesis predicts that although the extracellular signal, the growth factor, is applied homogeneously, an organized "dissipative structure" will emerge spontaneously in the responding tissue; this "symmetry breaking" in a reaction-diffusion system occurs precisely in the manner envisaged by Turing, where (cAMP, ATP) constitutes the "reaction-diffusion system". This Turing bifurcation explicates the recent experiments where a differentiated embryoid emerges from the mere immersion of frog animal caps in an homogeneous growth factor solution, and similar experiments on chicks. The "metabolic" patterns found by Child and colleagues also reflect dissipative structures arising in a (cAMP, ATP) reaction-diffusion system when interpreted in the light of modern biochemistry: in particular, the localized glycogen depletion reflects localized cAMP; localized redox, respiratory or susceptibility activity reflects localized ATP. The dramatic collapse of organized structure found by Child and colleagues, for example, when Planaria or a section of it is exposed to an homogeneous environment of a narcotic solution, and the reemergence of structure upon return to water, are explained on the basis of the violation or satisfaction of the Turing bifurcation conditions with respect to (cAMP, ATP), respectively. cAMP is the "activator", ATP is the "inhibitor", and together they mutually satisfy the four activator-inhibitor inequalities, including the all-important autocatalytic cAMP production, as well as the lateral inhibition condition. The functional significance of gap junctions is to generate a multicellular purely reaction-diffusion system for (cAMP, ATP) as envisaged by Turing. It is emphasized that localization and pattern formation occur intracellularly in gap junction-coupled cells and not, as often suggested, extracellularly, the latter localization being too fragile to be maintained for long enough, and soon succumbing to the mixing effect of convection and movement. The activator-inhibitor property of (cAMP, ATP) means that the spatial distribution of cAMP and ATP could be not only nonhomogeneous but also of the same shape.(ABSTRACT TRUNCATED AT 400 WORDS)

Mathematical model of morphogen electrophoresis through gap junctions

“…This model makes several other predictions that will be tested in the context of left-right patterning in the future, because the amount and distribution of serotonin, gap junctions, and ion transporters can be experimentally varied in this system. However, the analysis presented here can be used to model many other signaling systems in addition to serotonin; for example, other small molecules such as cAMP, ATP, and so on are known to pass through gap junctions (Cotrina et al, 1998(Cotrina et al, , 2000Braet et al, 2003;Bao et al, 2004) and have been suggested as candidate morphogens participating in the establishment of positional information (Schiffmann, 1989(Schiffmann, , 1991.…”

Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation

“…A classic paper by Alan Turing (Turing 1952) proposed that spatially periodic, temporally stable patterns emerging from the instability of a homogeneous steady state represent a mechanism for morphogenesis in living systems. Recent work (Agladze et al 1993; Sawai et al 2000; Schiffmann 2011) has analyzed the means by which the chemical gradients formed by a system of diffusing compounds (a long-range inhibitor plus a short-range activator) can also self-catalyze the creation of a pattern within a homogeneous cell field (Schiffmann 1991). Such symmetry-breaking and spatial self-organization might underlie anterior-posterior pattern formation during Drosophila embryogenesis, Hydra regeneration, amphibian organizer signaling and pigment patterns in the epidermis of numerous animals (Kondo 2002; Kondo et al 2009; Meinhardt 2000, 2001; Nakamasu et al 2009).…”

Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning

“…While Child was one of the first to propose a physical substratum for these fields - physiological gradients (Child, 1941b), recent data confirm that steady-state bioelectrical properties are likely an important component of this fascinating set of signals (Adams and Levin, 2012b; Levin, 2009, 2012). In addition to these, chemical gradients (De Robertis et al, 1991; Reversade and De Robertis, 2005; Schiffmann, 1991, 1994, 1997, 2008, 2011), shear flows (Boryskina et al, 2011), coherent photon fields (Fels, 2009; Popp, 2009), and gene expression profiles (Chang et al, 2002; Rinn et al, 2006) are additional candidates for mediators of field information during patterning. Nevertheless, formal morphogenetic field models, especially those incorporating specific mechanisms and making testable predictions, are not common.…”