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I revisit two theories of cell differentiation in multicellular organismspublished a half-century ago, Stuart Kauffman's global gene regulatory dynamics(GGRD) model and Roy Britten's and Eric Davidson's modular gene regulatorynetwork (MGRN) model, in light of newer knowledge of mechanisms of generegulation in the metazoans (animals). The two models continue to informhypotheses and computational studies of differentiation of lineage-adjacentcell types. However, their shared notion (based on bacterial regulatorysystems) of gene switches and networks built from them, have constrainedprogress in understanding the dynamics and evolution of differentiation. Recentwork has described unique write-read-rewrite chromatin-based expressionencoding in eukaryotes, as well metazoan-specific processes of gene activationand silencing in condensed-phase, enhancer-recruiting regulatory hubs,employing disordered proteins, including transcription factors, withcontext-dependent identities. These findings suggest an evolutionary scenarioin which the origination of differentiation in animals, rather than dependingexclusively on adaptive natural selection, emerged as a consequence of a typeof multicellularity in which the novel metazoan gene regulatory apparatus wasreadily mobilized to amplify and exaggerate inherent cell functions ofunicellular ancestors. The plausibility of this hypothesis is illustrated bythe evolution of the developmental role of Grainyhead-like in the formation ofepithelium.

Cell differentiation: what have we learned in 50 years?