Scientists Map a Grand Plan to Decode the Microtubule Cytoskeleton in Health and Disease

Microtubules are among the most intensively studied structures in cell biology, yet a striking paradox has emerged from decades of research: although scientists understand their molecular building blocks in remarkable detail, no one has been able to connect this atomic-scale knowledge to the larger question of how entire microtubule networks shape physiology, development and ageing in living organisms. A new Roadmap article published in Nature Reviews Molecular Cell Biology argues that the field has reached a turning point, and that only by integrating experimental and theoretical approaches across every spatial and temporal scale can researchers finally grasp how this ancient cellular scaffolding sustains life and how its failure drives a broad spectrum of human diseases.

The article, led by Carsten Janke of Institut Curie and Université Paris-Saclay together with Anna Akhmanova of Utrecht University and an international consortium of sixteen colleagues from institutions spanning Europe and the United States, lays out a coordinated agenda for the microtubule field. Its authors span structural biology, biophysics, cell biology, neuroscience, parasitology and computational modelling, reflecting their central conviction that progress will come not from any single discipline but from a deliberate fusion of them. The paper is punctuated by the admission that some of the most basic questions remain unexplored, including how the properties and functions of microtubules are affected by the chemical marks known as tubulin post-translational modifications, by disease-related mutations in tubulin genes, or by variation in the microtubule lattice itself.

Microtubules are hollow tubes assembled from αβ-tubulin dimers that stack into protofilaments, typically thirteen of which align laterally to form the wall of the polymer. What makes these structures extraordinary is their behaviour: individual microtubules stochastically switch between phases of growth and rapid shrinkage, a phenomenon called dynamic instability, which was first described by Tim Mitchison and Marc Kirschner in 1984. A stabilizing cap of GTP-bound tubulin at the growing plus end controls this behaviour, and its loss triggers catastrophic depolymerization. Beyond pure polymerization, microtubules can self-repair by incorporating new tubulin along damaged stretches of lattice, a property revealed in studies showing that lattice defects actually induce self-renewal and protect the polymers from destruction by molecular motors. These discoveries have transformed the view of microtubules from static beams into dynamic, self-healing machines.

The Roadmap emphasizes that microtubule function is not determined by the polymer alone but by a dense layer of regulation encoded on the tubulin subunit itself. Enzymes of the tubulin tyrosine ligase-like family decorate the unstructured carboxy-terminal tails of tubulin with modifications such as tyrosination, detyrosination, acetylation, glutamylation and glycylation, creating what has become known as the tubulin code. Recent structural work has shown, for example, that enzymes involved in polyglutamylation recognize microtubules through a quadrivalent mechanism that links microtubule geometry to the generation of localized modification patterns, and that protofilament-specific nanopatterns of these marks tune the mechanics of beating cilia. The Roadmap argues that understanding how this chemical language is written, read and erased across cellular contexts is one of the field’s most pressing challenges, particularly because disruptions in the code are now firmly linked to neurodegeneration, ciliopathies and other disorders.

Nowhere is the clinical relevance more evident than in the nervous system. Neurons depend on microtubule tracks for the long-range transport of organelles, messenger RNAs and signalling endosomes along axons and dendrites, a process powered by kinesin and dynein motor proteins. Mutations in tubulin genes such as TUBA1A cause lissencephaly, a severe developmental brain malformation, by perturbing neuronal migration, and variants in a growing list of tubulin genes underlie a spectrum of neurodevelopmental disorders collectively known as tubulinopathies. Defective axonal transport is a shared hallmark of motor neuron diseases, and recent work has shown that excessive polyglutamylation of tubulin in the brain is sufficient to drive neurodegeneration by disrupting transport, while restoring the balance of these modifications can rescue affected neurons. The Roadmap positions a systems-level understanding of these processes as essential for translating molecular insight into therapies.

The heart and the immune system tell equally compelling stories. In beating cardiomyocytes, detyrosinated microtubules act as load-bearing elements that buckle under contraction and stiffen the cell, and suppressing this modification improves cardiac function in models of heart failure. In immune cells, microtubule networks orchestrate cell shape, migration and the directed release of lytic granules by natural killer cells, while platelets, whose tubulin repertoire is dominated by the β1-tubulin isotype, rely on precisely regulated microtubule assembly during their biogenesis; mutations in the TUBB1 gene cause congenital macrothrombocytopenia and thyroid dysgenesis. The Roadmap argues that these tissue-specific roles cannot be understood piecemeal and demand approaches that bridge the molecular properties of tubulin to the physiology of whole organs.

Technological innovation sits at the centre of the proposed strategy. Cryo-electron microscopy and cryo-electron tomography now reveal microtubules and their associated proteins at near-atomic and in situ resolution, while expansion microscopy and ultrastructure expansion microscopy allow researchers to visualize centrioles, cilia and mitotic spindles in whole cells and tissues with nanometre precision. In vitro reconstitution, a tradition stretching back to the pioneering work of Tim Mitchison and Marc Kirschner and continued in landmark experiments showing that purified microtubules and motors can self-organize into asters and vortices, remains indispensable for dissecting minimal systems. These experimental approaches are increasingly paired with computational and physical models that simulate spindle assembly, microtubule network organization and chromosome movement, and the Roadmap calls for tighter coupling between modelling and experiment, including the development of virtual cells powered by artificial intelligence.

Recombinant tubulin technology is highlighted as a particularly transformative advance. For decades, biochemists were limited to native tubulin purified from brain tissue, a mixture of isotypes and modifications that obscured cause and effect. The ability to produce functional human tubulin dimers in defined isotypes, with controlled post-translational modifications, has now enabled researchers to show directly that different isotypes confer distinct dynamic properties, that detyrosination tunes microtubule stability through selective recruitment of associated factors, and that systematic mutagenesis can map the functional landscape of disease-linked variants. Combined with deep mutational scanning and artificial-intelligence-driven phenotyping, the authors argue, these tools will allow the effects of every clinically observed tubulin mutation to be predicted and tested, a goal that seemed out of reach only a few years ago.

The Roadmap also looks beyond animal cells, drawing attention to the diversity of microtubule arrays across eukaryotes, from the cortical arrays that guide plant cell morphogenesis to the subpellicular arrays of trypanosomes and the specialized mitotic machinery of parasites. Comparative studies of parasites such as Plasmodium have revealed that adaptations in tubulin sequence generate distinct microtubule architectures, mechanics and drug susceptibilities, opening avenues for species-selective therapeutics. The authors contend that this evolutionary breadth is not a curiosity but a resource: organisms that build microtubules with unusual lattices, modifications or assembly mechanisms offer natural experiments that can illuminate principles hidden in familiar model systems.

Ultimately, the Roadmap is an invitation to think bigger. Its authors conclude that the microtubule cytoskeleton will continue to inspire scientists for decades precisely because so many fundamental questions remain open: how microtubule arrays are organized and diversified in different cell types, how the tubulin code is orchestrated across space and time, how mechanical forces reshape and stabilize microtubule lattices in living cells, and how all of this integrates into the physiology of tissues and organisms in health, ageing and disease. By bridging the atomic structure of the tubulin dimer with the behaviour of mitotic spindles, migrating neurons and beating hearts, the field aims to transform its fragmented molecular knowledge into a coherent systems-level picture, one that could reshape how disorders ranging from neurodegeneration and cancer to ciliopathies and heart failure are understood and treated.

The historical depth of the field is worth appreciating. Microtubules were first visualized in the late nineteenth and early twentieth centuries, but their protein building block was only identified in the late 1960s, when colchicine-binding assays led to the isolation of what was soon named tubulin, and amino-acid analysis of sperm flagella confirmed it as the universal subunit of the polymer. The discovery of dynamic instability two decades later established that these polymers are fundamentally nonequilibrium structures, a insight that continues to shape how spindle assembly and chromosome movement are understood today.

Equally important is the cast of regulatory proteins that act on microtubules. Microtubule-associated proteins such as tau can condense on the lattice in regulated phases, altering how motors and severing enzymes engage the polymer, while enzymes that cut microtubules generate new seeds and reshape networks. Proteins like doublecortin, which is mutated in human brain malformations, illustrate how even lattice geometry itself can be read selectively, recognizing only specific protofilament numbers. These layered interactions, spanning motors, maps, severing enzymes and modifying enzymes, form the mechanistic vocabulary that any systems-level account of the cytoskeleton will ultimately need to integrate.

Subject of Research: Systems-level integration of microtubule cytoskeleton structure, regulation and function in physiology and disease

Article Title: Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease

Article References: Janke, C., Akhmanova, A., Bartolini, F., Bodakuntla, S., Del Bene, F., Hamel, V., Mitchison, T. J., Müller-Reichert, T., Nédélec, F., Nogales, E., Pigino, G., Roll-Mecak, A., Schiavo, G., Surrey, T., & Lansky, Z. (2026). Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-026-01011-w

Image Credits: AI Generated

DOI: 10.1038/s41580-026-01011-w

Keywords: microtubules, tubulin code, post-translational modifications, dynamic instability, axonal transport, tubulinopathies, ciliopathies, neurodegeneration, mitotic spindle, cryo-electron tomography, in vitro reconstitution, systems biology