The protein has been named MSEP, and it is produced from an RNA molecule called ARHGEF17-AS1. According to the two new studies, published in the journal Cell Reports, both the RNA molecule and the protein it encodes help maintain the mitotic spindle, the cellular machinery that pulls chromosomes apart when a cell divides. When this structure fails, chromosomes can be distributed unevenly between daughter cells, a hallmark of many diseases, including cancer. The fact that a single genetic locus produces two functional molecules, each supporting the same structure through different routes, makes this a rare and intriguing example of what researchers describe as a bifunctional locus.

Sagar Mahale, a researcher at Sahlgrenska Academy at the University of Gothenburg and first author of both studies, emphasized the surprise embedded in the result. What is particularly interesting, he noted, is that the RNA molecule and the protein do not perform the same job. They act through different pathways in the cell, but both help maintain the same essential structure when the cell divides. That distinction matters because it means the two products of the same gene cannot simply substitute for one another; each contributes something the other does not.

To disentangle these overlapping roles, the team designed experiments that targeted the RNA and the protein separately in cultured cells. By reducing the RNA molecule directly in one set of experiments and disrupting MSEP production in another, the researchers could observe which cellular defects followed from losing the RNA alone, which followed from losing the protein alone, and which required the loss of both. This separation is technically demanding, because many conventional methods that silence a gene remove both its RNA and any protein it encodes at the same time, blurring the very distinction the researchers wanted to study.

The results showed that both products converge on mitotic spindle integrity. The spindle is built from microtubules, dynamic protein filaments that attach to chromosomes and generate the forces needed to separate them into the two emerging daughter cells. Its assembly and stability depend on a large cast of regulatory proteins, motor enzymes, and structural components, and even small disruptions can lead to missegregated chromosomes. The Gothenburg findings indicate that ARHGEF17-AS1 contributes to spindle organization through its own RNA-based functions, while MSEP supports the same organization as a protein, each acting through distinct molecular pathways.

The discovery fits into a broader shift in genetics. For decades, the central dogma of molecular biology encouraged researchers to divide the genome neatly into genes that encode proteins and everything else. Large-scale sequencing projects, however, revealed that a substantial fraction of the genome is transcribed into RNA even though most of those transcripts were assumed to be non-coding. Improvements in sequencing accuracy, ribosome profiling, and mass spectrometry have now made it possible to detect small or unusual proteins translated from transcripts once labeled as noise. These hidden proteins, sometimes called microproteins or alternative open reading frame products, are increasingly being shown to carry out real biological functions rather than serving as evolutionary leftovers.

What makes the MSEP case especially compelling is the dual functionality of its source locus. The ARHGEF17-AS1 transcript not only carries the code for a protein but also performs an independent role in the cell, contributing to spindle integrity on its own. This arrangement, in which one genetic location yields both a coding and a non-coding function, expands the classical definition of a gene and raises questions about how many other transcripts currently annotated as non-coding may harbor similar hidden products with meaningful roles.

The cancer connection emerged naturally from the biology. Because cancer cells depend on successful, repeated division to proliferate, any factor that supports the mitotic spindle is a potential vulnerability. When the researchers examined cancer cell lines, they found that MSEP levels were higher in the cancer cells than in normal cell lines. When they reduced the amount of ARHGEF17-AS1 RNA or disrupted MSEP production in cultured cervical cancer cells, the cells showed reduced growth and proliferation. In other words, interfering with either product of the bifunctional locus slowed the cancer cells down, suggesting that rapidly dividing cells may be unusually reliant on this hidden protein and its RNA.

Chandrasekhar Kanduri, a professor at Sahlgrenska Academy at the University of Gothenburg and senior author of both studies, cautioned against jumping to clinical conclusions. The findings, he noted, raise the question of whether certain tumors are particularly dependent on MSEP to continue dividing, but it is too early to say whether the protein could become a target for future treatments. That restraint reflects the standard caution of early-stage cell biology: what happens in a culture dish does not always translate to living tissue, and therapeutic exploitation of a newly discovered protein requires years of validation work.

Indeed, the researchers themselves stress that the findings are based on studies of cultured cells, and further research is needed to determine the roles of the RNA molecule and MSEP in tumors and other tissues. The next steps will likely involve examining patient tumor samples to see whether MSEP expression correlates with aggressive disease, testing the protein’s function in animal models, and working out the precise molecular mechanisms by which the RNA and the protein each stabilize the spindle. If those efforts confirm the cultured-cell results, the work could open a new line of cancer research focused not on well-known oncogenes but on the hidden proteome, the layer of small, overlooked proteins that modern technology is only now bringing into view. For now, the discovery stands as a reminder that the genome still holds surprises, and that some of the most important players in fundamental cell biology have been waiting, unannotated, in transcripts everyone had already catalogued and set aside.

Subject of Research: Discovery of the hidden protein MSEP, encoded by the non-coding RNA ARHGEF17-AS1, and its role in mitotic spindle organization and cell division

Article Title: Hidden protein helps cells divide correctly

Article References: Hidden protein helps cells divide correctly. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: MSEP, ARHGEF17-AS1, hidden proteome, non-coding RNA, mitotic spindle, cell division, cancer research, University of Gothenburg, Cell Reports, bifunctional locus, cervical cancer, protein discovery

The team assembled measurements from twenty-five eukaryotic species spanning yeasts, animals and plants, drawing on published images and new morphometric analyses of spindle length, spindle width and the dimensions of the metaphase plate, the equatorial plane where chromosomes line up before segregation. When they plotted metaphase plate width against genome size on logarithmic axes, the data collapsed onto a straight line, revealing a power law with an exponent of approximately one third. The correlation was remarkably tight, with an R-squared value of 0.94. In practical terms, this means that when the amount of DNA in a genome increases a thousand-fold, the width of the structure that accommodates it grows only about ten-fold. Sublinear scaling of this kind is a hallmark of geometric constraints, and it hinted at an underlying physical mechanism rather than a purely biochemical one.

The clue to that mechanism came from the geometry of the chromosomes themselves. Previous work had shown that condensed mitotic chromosomes maintain a roughly uniform chromatin density of around ninety megabase pairs per cubic micrometre across species. The new analysis extended this observation to the level of the entire metaphase plate: plate volume scaled almost linearly with genome size, with an exponent of 0.96, and the effective density of the plate was roughly constant across organisms. The plate also maintained a conserved shape, with a width-to-thickness aspect ratio of about 1.9. Crucially, chromosome number played almost no role in the scaling. Species with similar chromosome counts but different genome sizes had very different plate widths, while species with similar genome sizes but chromosome numbers ranging from six to forty-six had nearly identical plates. It is the total volume of chromatin, not how it is parcelled into individual chromosomes, that dictates spindle geometry.

To explain the one-third exponent, the researchers built a physical model of the spindle in which each chromosome is represented as a compressible elastic sphere, attached to microtubule bundles that extend between the two spindle poles. The microtubules, through their bending stiffness, push the chromosomes inward toward the spindle axis, while the chromosomes, packed tightly together in the metaphase plate, push back against one another through steric repulsion. The equilibrium between microtubule bending forces and interchromosome pushing forces determines the positions of the chromosomes and hence the width of the plate and the spindle. Because chromosome volume is proportional to genome size, the characteristic length of a chromosome grows with the cube root of the genome, and the model naturally predicts a power-law exponent close to the observed 0.33. When the model was calibrated on human spindle parameters and extrapolated across four orders of magnitude of genome size, it predicted an exponent of 0.37, in close agreement with the comparative data.

The model made a second, counterintuitive prediction: if the total volume of chromatin is held constant while the number of chromosomes is varied, the metaphase plate width should remain roughly constant. This was confirmed by comparing species with similar genome sizes but very different chromosome numbers. Conversely, when chromosome number increases at constant individual chromosome volume, meaning more total chromatin, the model predicted a power-law widening with an exponent of 0.43, and experiments matched this behaviour. The estimated interchromosome pushing forces were in the range of hundreds of piconewtons, comparable to the pulling forces that molecular motors and microtubule depolymerization exert at kinetochores, the protein structures that link chromosomes to spindle fibres.

Experimental tests followed four complementary strategies. First, the team generated polyploid human cells, including hypotetraploid and hypooctaploid derivatives of the non-transformed RPE1 line and the tumour-derived HCT116 line, using carefully designed protocols that prevented centriole overduplication so that cells divided with bipolar spindles. Metaphase plate width increased robustly with ploidy in every case, and cell-by-cell analysis using nuclear area as a proxy for ploidy yielded a power-law exponent of 0.29, matching the cross-species value. Second, the researchers exploited natural ploidy variation in patient-derived colorectal cancer organoids and found the same scaling relationship. Third, by acutely reactivating the motor protein CENP-E in cells whose chromosomes had been stranded at the spindle poles, they watched in real time as chromosomes entered the plate, and both plate width and chromatin density rose in step with the increasing chromosome number. Fourth, forcing cells into mitosis with an unreplicated genome, so that most chromatin remained uncondensed in the cytoplasm, produced spindles that were thirty-one percent thinner without any change in cell size.

Perhaps the most dramatic test involved physically squeezing the spindles. The team compressed metaphase cells with a soft agarose gel, reducing spindle height by roughly forty-four percent within a minute. If chromosomes truly push against one another, compressing the cell should squeeze the plate sideways, and that is exactly what happened: the metaphase plate widened by about thirty percent and thickened by about fifty percent, while spindle length stayed unchanged. The angle between the outermost microtubule bundles at the poles increased, consistent with the model’s prediction that microtubules pivot around freely jointed pole attachments. When the compression was released, the spindle partially recovered its original shape. Spindles with unreplicated genomes widened less under compression, as the model predicted for softer, smaller chromatin masses. Compressed cells took longer to complete metaphase, suggesting that excessive interchromosome pushing forces impede the machinery of division.

The study also clarified that spindle length and spindle width are governed by independent mechanisms. Acute depolymerization of microtubules with nocodazole collapsed spindle length by sixty-five percent within minutes but left spindle width and plate width untouched, showing that width is maintained by the mechanical properties of chromatin rather than by microtubule-generated forces. Osmotic shocks, which alter cytoplasmic density, compressed or relaxed the plate and spindle in ways that decoupled length from width. Perturbing dozens of microtubule-associated proteins changed spindle length by up to one hundred percent while shifting width by only about twenty percent. In meiosis, the picture held as well: metaphase I plates, carrying twice the chromatin of metaphase II, were twenty-three percent wider in human oocytes and thirty-three percent wider in mouse oocytes, with spindle length differing by no more than seven percent.

The implications reach well beyond basic cell biology. The authors propose that chromosome crowding explains why animal cells round up before dividing, creating space for the spindle, and why eukaryotes with larger genomes evolved open mitosis, in which the nuclear envelope disassembles. It may also explain why polyploid cells, common in the human liver and frequent in tumours, can divide at all: the spindle simply widens to accommodate the extra chromatin, and adapted polyploid cells enlarge their spindles further with a distinct transcriptional programme. In plants, whose spindles have unfocused poles and experience weaker compression forces, the mechanism may have facilitated the repeated whole-genome duplications that drive speciation. A single physical principle, chromosomes fighting for space in the metaphase plate, appears to underpin how life divides genomes large and small.

Subject of Research: Power-law scaling of mitotic spindle dimensions with genome size across eukaryotes, driven by interchromosome pushing forces from chromosome crowding at the metaphase plate

Article Title: Power-law scaling of mitotic spindles with genome sizes across eukaryotes is driven by chromosome crowding

Article References: Gudlin, L., Vukušić, K., Novak, M., Trupinić, M., Ljulj, M., Dundović, I., Petelinec, A., Petrušić, L., Hertel, A., van Ravesteyn, T., Trakala, M., Kops, G. J. P. L., Storchová, Z., Tambača, J., Pavin, N., & Tolić, I. M. (2026). Power-law scaling of mitotic spindles with genome sizes across eukaryotes is driven by chromosome crowding. Nature Cell Biology. https://doi.org/10.1038/s41556-026-02005-8

Image Credits: AI Generated

DOI: 10.1038/s41556-026-02005-8

Keywords: mitotic spindle, chromosome crowding, genome size, power-law scaling, metaphase plate, microtubules, polyploidy, cell division, biophysics, eukaryotes, meiosis, chromatin density

The clinical starting point came from three patients with neurodevelopmental disorders who carried damaging MSL2 variants. Two harbored protein-truncating variants, one a de novo frameshift and one a stop-gain mutation with undetermined inheritance, while the third carried a de novo 83-kilobase microdeletion spanning both MSL2 and the neighboring PCCB gene. All three children presented with moderate to severe intellectual disability, language impairment, and motor delay, and two showed autism or autistic features. Critically, magnetic resonance imaging revealed white matter abnormalities in every patient, ranging from a thin corpus callosum and punctate frontal hyperintensities in the oldest patient to diffuse symmetrical T2 hyperintensity, ventricular enlargement, and widespread polymicrogyria in a seven-month-old infant. The consistency of these imaging findings across patients with different mutation types underscored white matter vulnerability as a hallmark of MSL2-related disease.

To probe what the variants actually do to cells, the team turned to immortalized lymphocytes available from the patient carrying the microdeletion. Western blotting and immunofluorescence showed markedly reduced MSL2 protein compared with four age- and sex-matched healthy controls, and the levels of two histone marks that MSL2 helps regulate, H4K16ac and H3K4me3, trended downward in the patient’s cells. These marks are chemical embellishments on histone proteins that flag chromatin as open and transcriptionally active, so their reduction signaled that the mutation genuinely impairs MSL2’s epigenetic function rather than merely removing one copy of the gene. The finding gave the researchers a molecular fingerprint to hunt for in the brain.

That hunt required a new animal model, because mice lacking Msl2 from conception die as embryos, masking any role the gene plays in specific cell types. The team instead crossed mice carrying a floxed Msl2 allele with Olig1-Cre mice, deleting a critical exon that encodes both the N-terminal RING finger domain and the C-terminal CXC domain, thereby producing a loss-of-function mutation exclusively in the oligodendrocyte lineage. Quantitative PCR and western blotting confirmed that Msl2 expression collapsed in purified precursor cells from these conditional knockouts, while MSL2 protein remained intact in mature neurons, proving the deletion was cell-type specific. The researchers also tracked where and when MSL2 acts normally, finding that Msl2 transcripts were far more abundant in white matter structures such as the corpus callosum and optic nerve than in cortex at postnatal day 7, peaked in the first two postnatal weeks, and were highest in newly formed oligodendrocytes before declining in mature myelin-producing cells.

What happened when the gene was removed was striking. The density of SOX10-positive oligodendrocyte lineage cells was normal at birth but fell significantly from postnatal day 7 through day 50 in both the corpus callosum and the cortex. The proportion of CC1-positive mature oligodendrocytes dropped, myelin basic protein levels declined sharply, and electron microscopy at postnatal day 40 revealed fewer myelinated axons with thinner myelin sheaths and higher g-ratios, a quantitative measure of reduced myelin thickness. TUNEL assays ruled out increased cell death, but EdU incorporation showed far fewer proliferating precursor cells in the mutants, and fewer of the cells that did incorporate EdU went on to become MBP-positive oligodendrocytes. In purified cultures treated with thyroid hormone to drive differentiation, Msl2-deficient cells showed intrinsically reduced capacity to become CNPase- and MBP-positive oligodendrocytes, and an inducible knockout triggered at the onset of differentiation still impaired maturation, indicating that MSL2 is required both for proper cell division and for the initiation of differentiation.

The behavioral fallout mirrored the cellular damage. In the three-chamber sociability test, mutant mice showed no preference for a stranger mouse over an empty chamber and failed to recognize social novelty, while the resident-intruder test revealed strong social avoidance and the self-grooming test revealed repetitive behavior, together recapitulating the core diagnostic domains of autism spectrum disorder. Open field and elevated plus maze tests showed heightened anxiety, the tail suspension test and sucrose preference test indicated depressive-like states, and notably, novel object recognition remained intact, suggesting that cognition was spared even as social and emotional behaviors were disrupted. This constellation of social withdrawal, repetitive grooming, and comorbid anxiety and depression makes the conditional knockout a potentially valuable model for studying how epigenetically regulated myelin contributes to autism.

The mechanistic core of the study came from integrated transcriptomic and epigenomic profiling of purified precursor cells. RNA sequencing identified 1,166 genes upregulated and 327 downregulated after Msl2 loss, and gene ontology analysis of the downregulated set pointed squarely at cell cycle, cell division, mitotic spindle, and myelin sheath terms. Among the affected genes were Aspm, a microcephaly-associated spindle assembly factor; Tpx2, which nucleates spindle microtubules; and Bub1b, a kinase essential for the spindle-assembly checkpoint. Cell synchronization experiments made the consequence concrete: while nearly 70 percent of phospho-histone H3-positive control cells reached metaphase, only about 25 percent of mutant cells did, with most stalling in prophase or prometaphase and metaphase cells displaying loose chromosome compaction, triple or multipolar spindles, and twisted spindle architectures. Meanwhile, the upregulated genes were enriched for inflammatory response, innate immune response, and cytokine activity, with chemokines such as Cxcl1, Cxcl2, Ccl4, and Ccl20 elevated, hinting that MSL2 loss may endow precursor cells with immunomodulatory properties that could exacerbate neuroinflammation.

Epigenomic mapping revealed which histone mark carries the weight. ChIP-seq for H3K4me3 showed that although the genomic distribution of peaks was broadly preserved, peak signals dropped dramatically near transcription start sites after Msl2 deletion, and genes losing the mark were enriched for myelination, oligodendrocyte differentiation, cell proliferation, and mitotic G2/M transition terms. Cross-referencing with the transcriptome showed that 177 genes with reduced H3K4me3 were also transcriptionally downregulated, accounting for nearly 36 percent of all downregulated genes. By contrast, H4K16ac, the canonical product of the MSL-MOF complex, was only mildly reduced and overlapped with just 12 percent of downregulated genes, while H2BK120ub, an indirect target of MSL2’s ubiquitin ligase activity, showed minimal concordance with either H3K4me3 loss or transcriptional change. The data collectively reposition H3K4me3, rather than H4K16ac, as the dominant downstream effector of MSL2 in oligodendrocyte lineage cells.

Proteomics added an unexpected twist to the mechanism. Co-immunoprecipitation coupled with mass spectrometry identified 160 MSL2-interacting proteins in precursor cells, including the expected partner KAT8, also known as MOF, but also ASH2L and RBBP5, the core subunits of the COMPASS-like H3K4 methyltransferase complex, and SOX10, the master transcription factor of the oligodendrocyte lineage. Western blotting on MSL2 immunoprecipitates validated all of these interactions. This suggests a previously unrecognized model in which MSL2 physically recruits the H3K4 methylation machinery to myelination and cell cycle genes, with SOX10 potentially guiding the complex to its oligodendrocyte-specific targets, independent of MSL2’s E3 ubiquitin ligase activity toward H2B.

The implications extend well beyond a rare syndrome. Because MSL2 governs the transition from proliferating precursor cells to differentiating oligodendrocytes rather than lineage commitment itself, modulating MSL2 complex activity could, in principle, enhance myelination programs not only in MSL2-related neurodevelopmental disorders but also in conditions involving demyelination. The study’s authors caution that more than 60 percent of downregulated genes did not show significant H3K4me3 reduction, leaving room for additional mechanisms such as H3K79 methylation or MSL2’s proposed role in protecting regulatory regions from DNA methylation. Still, by linking patient genetics, cell-autonomous mouse genetics, cell cycle biology, and chromatin profiling into a single coherent story, the work transforms MSL2 from a gene of uncertain function into a defined epigenetic regulator of the brain’s insulation, and it offers the white matter defects seen on MRI in affected children their first clear molecular explanation.

Subject of Research: The role of the chromatin regulator MSL2 in oligodendrocyte precursor cell cycle control, H3K4me3-mediated gene regulation, and white matter defects in neurodevelopmental disorders.

Article Title: MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders

Article References: Yuan, J., Dong, Y., Zhang, K., Wei, Z., Zhang, Z., Zhang, M., Luo, S., Jiang, S., Peng, Y., Wu, X., Yvan, H., Goel, H., Zhang, E., The Australian Undiagnosed Diseases Network (UDN-Aus), Guo, H., Wu, S., & Zhao, X. (2026). MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01858-1

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01858-1

Keywords: MSL2, oligodendrocytes, H3K4me3, myelination, neurodevelopmental disorders, autism spectrum disorder, white matter, epigenetics, cell cycle, mitotic spindle, conditional knockout mice, chromatin regulation

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