Vimentin's Journey from "Background Scaffold" to Multi-Scale Regulator of Neuronal Growth and Function: Historical, Conceptual and Epistemic Perspectives.

Neurons achieve their highly polarized architecture by coordinating cytoskeletal systems across space and time, enabling axons to extend over remarkable distances and dendrites to elaborate complex arbours. Early neuroanatomists described intracellular "neurofibrils," yet these structures remained poorly understood until electron microscopy resolved them into three distinct polymer systems: microtubules, actin filaments, and intermediate filaments. Although this framework clarified neuronal ultrastructure, it simultaneously established a conceptual hierarchy in which microtubules and actin were regarded as the principal drivers of neurite growth, while intermediate filaments were relegated to a passive, supportive role. Unlike prior reviews that document vimentin dynamics primarily from a cell-biological standpoint, this review integrates historical, conceptual, and epistemological perspectives to examine both how and why that hierarchy arose and how it has been dismantled. This review traces how that hierarchy arose and why it has been increasingly reconsidered in favour of intermediate filaments, focusing on vimentin as a case study. Evidence from live cell imaging, molecular manipulation, and genetic models shows that vimentin is dynamically regulated rather than static. Vimentin networks remodel continuously, exchange subunits with soluble pools, and move in coordination with microtubules. Most recently, sparse single-filament labelling combined with correlative volume electron microscopy has demonstrated that individual vimentin filaments remain motile even within dense perinuclear networks previously assumed to be static, a finding that fundamentally redefines what filament density implies about cytoskeletal organization. In neural and neural precursor cells, vimentin expression is developmentally regulated and is prominent during early differentiation stages associated with neurite initiation giving way to neurofilaments in mature neurons. Functional studies further link vimentin to neurite formation and extension, cytoskeletal coordination, organelle positioning, and cellular stress responses. Philosophical analysis reveals that these empirical advances were inseparable from shifts in imaging technology and conceptual framing, and that epistemic risks including model dependency and confirmation bias can be mitigated through methodological pluralism and explicit model disclosure. Taken together, these findings support a revised understanding of intermediate filaments as active, context-dependent contributors to neuronal development and plasticity, and illustrate the value of integrating biological evidence with historical and philosophical reflection.