Cell differentiation: What have we learned in 50 years?

Abstract

I revisit two theories of cell differentiation in multicellular organisms published a half-century ago, Stuart Kauffman's global gene regulatory dynamics (GGRD) model and Roy Britten's and Eric Davidson's modular gene regulatory network (MGRN) model, in light of newer knowledge of mechanisms of gene regulation in the metazoans (animals). The two models continue to inform hypotheses and computational studies of differentiation of lineage-adjacent cell types. However, their shared notion (based on bacterial regulatory systems) of gene switches and networks built from them, have constrained progress in understanding the dynamics and evolution of differentiation. Recent work has described unique write-read-rewrite chromatinbased expression encoding in eukaryotes, as well metazoan-specific processes of gene activation and silencing in condensed-phase, enhancer-recruiting regulatory hubs, employing disordered proteins, including transcription factors, with context-dependent identities. These findings suggest an evolutionary scenario in which the origination of differentiation in animals, rather than depending exclusively on adaptive natural selection, emerged as a consequence of a type of multicellularity in which the novel metazoan gene regulatory apparatus was readily mobilized to amplify and exaggerate inherent cell functions of unicellular ancestors. The plausibility of this hypothesis is illustrated by the evolution of the developmental role of Grainyhead-like in the formation of epithelium.

Precartilage condensation during limb skeletogenesis occurs by tissue phase separation controlled by a bistable cell-state switch with suppressed oscillatory dynamics

“…That is, they do not differ simply by the concentrations of the molecular species controlling their partitioning. One hallmark of cell differentiation is the recruitment and exaggerated expression of ancestral cell functions so as to set a population of cells apart from those spatially contiguous to them and adjacent to them in a developmental lineage (Newman (2020)). In the case described here, the incipient functional differentiation represented by the increased randomly oriented velocity of the protocondensed cells is clearly transient: the cell velocity in definitive fibronectin-rich condensations, and certainly in the terminally differentiated cartilage that arises from them will be much reduced, tending to zero.…”

“…The compositional differences (i.e., location in state space) between attractor states of a multicomponent dynamical system are a purely mathematical effect. Cell types, in contrast, embody coherent functions within their respective tissues: contractile muscles, supportive bones, excitable nerves and so forth, and it is implausible that the suites of gene products required to support the coordinated tasks of any one cell type, let alone all of them, would arise simply as a consequence of dynamical partitioning (Newman (2020)). Furthermore, the different cell types within an organ (e.g., in the lung, the gas permeable type 1 pneumocytes, the capillary-lining endothelium, and the surfactant-producing type 2 pneumocytes of a lung air sac), need to operate as a unit (Ross et al (2002)).…”

“…Furthermore, the different cell types within an organ (e.g., in the lung, the gas permeable type 1 pneumocytes, the capillary-lining endothelium, and the surfactant-producing type 2 pneumocytes of a lung air sac), need to operate as a unit (Ross et al (2002)). It is highly unlikely that mathematically determined attractor states of a dynamical system would functionally coordinately in such a fashion (Newman (2020)).…”

Multiscale modeling of vertebrate limb development

“…Several features of developmental gene regulation resist modeling by conventional mathematical frameworks: lack of stoichiometry and mass action, and changeability of network topology, for example (reviewed in Newman, ). This prevents drawing any inferences about the global properties of the regulatory genome of an organism, for example, identifying its attractors with the organism's full array of cell types as has been proposed (Bornholdt & Kauffman, ; Kaneko & Yomo, ; Kauffman, ).…”

Beyond What Your Retina Can See: Similarities of Retinoblastoma Function between Plants and Animals, from Developmental Processes to Epigenetic Regulation

“…The formation of any organ relies on two different but interlinked cellular processes: cell proliferation and cell differentiation. Proliferation produces all the cells that later will acquire fates, specialized functions, and morphologies through differential gene expression during cell differentiation [ 147 , 148 ]. pRb has been widely studied in proliferation and, recently, its participation in many different animal differentiation processes in the eye, brain, peripheral nervous system, muscle, liver, placenta, lung, cerebellum, pituitary gland, and heart has been elucidated ( Figure 3 A) [ 149 , 150 , 151 , 152 , 153 , 154 ].…”