Repurposing of Kinetochore and SAC Proteins in Neurodevelopment

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Great! I'll gather research on how highly conserved kinetochore and spindle assembly checkpoint proteins have been repurposed for developmental roles beyond cell division, particularly in neurodevelopment and other developmental processes. The focus will be on model organisms such as C. elegans, Drosophila, mice, zebrafish, yeast, cell culture, and organoids, with an emphasis on image-based and genetic studies. The review will take an evolutionary perspective while briefly touching on biomedical applications. I’ll structure it like a high-impact biology journal review (e.g., Nature). I'll let you know when the research is ready for review.

Introduction

Kinetochore and spindle assembly checkpoint (SAC) proteins are classical guardians of mitosis, ensuring accurate chromosome segregation. The kinetochore is a multiprotein complex at the centromere that captures spindle microtubules and withstands pulling forces, thus enabling equal chromosomal partitioning

pmc.ncbi.nlm.nih.gov. SAC proteins, including Bub1/BubR1, Mad1/Mad2, and Aurora kinases, monitor microtubule attachment and tension, halting anaphase onset until all chromosomes are properly attachedwww.frontiersin.orgwww.frontiersin.org. These systems are highly conserved from yeast to humans, underscoring their fundamental importance in cell divisionpmc.ncbi.nlm.nih.gov. Historically, these proteins were not thought to function outside of cell cycle contextspmc.ncbi.nlm.nih.gov. However, emerging evidence supports an exciting hypothesis: during evolution, many kinetochore and SAC proteins have been co-opted for developmental roles in multicellular organisms. This review explores how these “mitotic” proteins have been repurposed in processes like neuronal differentiation, morphogenesis, and organ development. We highlight genetic and imaging studies across model organisms – from yeast and C. elegans to Drosophila, zebrafish, mice, and human cell models – that reveal surprising functions of these proteins beyond cell division. We also discuss mechanistic insights into how new functions arose and their evolutionary significance. Figure 1 provides a schematic overview of this concept, summarizing key examples of kinetochore/SAC protein repurposing in development (e.g. neuron morphogenesis vs. mitosis). Together, these findings support a paradigm shift: proteins traditionally viewed as exclusive to the mitotic apparatus also play direct roles in developmental pathways, hinting at an evolutionary strategy of molecular “tool reuse” to drive complex organismal development.

Kinetochore and SAC Proteins in Neurodevelopment

Neural progenitor maintenance and cell division fidelity: In the developing nervous system, maintaining a pool of proliferative neural progenitors is critical. Conserved SAC components ensure these progenitors divide without catastrophic errors. For example, BubR1 (an essential SAC kinase) is required to prevent premature anaphase and aneuploidy in neural stem cells. Conditional BubR1 deletion in the mouse embryonic cortex leads to massive progenitor death and cortical thinning (microcephaly)

www.frontiersin.org. Human patients with mutations in BUB1 or BUBR1 similarly exhibit primary microcephaly and neurodevelopmental delay, likely due to abnormal progenitor mitoses and p53-independent apoptosiswww.frontiersin.orgpmc.ncbi.nlm.nih.gov. These findings indicate that the canonical checkpoint role of Bub1/BubR1 is indispensable during brain development to ensure neural progenitor viability and expansion. Intriguingly, beyond simply safeguarding mitoses, some SAC proteins actively influence the balance between progenitor proliferation and differentiation. In Drosophila neural stem cell (neuroblast) lineages, the APC/C co-activator Cdh1 (Fizzy-related, Fzr) drives the transition from progenitor to differentiated neuron. Fzr/Cdh1 is an evolutionarily conserved protein that here promotes ganglion mother cell (GMC) differentiation into neuronswww.frontiersin.org. Loss of Fzr in neuroblasts blocks neuron production – mutant progenitors fail to exit the cell cycle, accumulate mitotic regulators (e.g. Polo kinase), and lose the differentiation factor Prosperowww.frontiersin.org. Notably, knocking down core APC/C subunits or the mitotic coactivator Cdc20 did not replicate this phenotype, suggesting a specialized, non-mitotic role for APC/C^Cdh1 in neuronal differentiationwww.frontiersin.org. Thus, core checkpoint machinery can be retuned in neural progenitors to actively terminate proliferation and initiate neuron-specific gene programs.

Differentiation, migration, and neurite outgrowth: Once neural progenitors exit the cell cycle, several kinetochore proteins take on completely new jobs in post-mitotic neurons. Recent work has unveiled a conserved requirement for kinetochore complexes in neuronal maturation. In Drosophila embryos, forward genetic screens unexpectedly identified kinetochore genes as regulators of synapse formation

pmc.ncbi.nlm.nih.gov. Mutations in multiple kinetochore components – spanning inner kinetochore (e.g. Mis12 complex) to outer kinetochore (Ndc80 complex, Knl1) – cause abnormal synaptic morphology at the neuromuscular junction (NMJ)pmc.ncbi.nlm.nih.gov. Specifically, motor neuron axon terminals overextend and fail to form proper synaptic boutons when kinetochore proteins are impairedpmc.ncbi.nlm.nih.gov. These phenotypes arise in post-mitotic neurons, indicating a direct role in synaptogenesis rather than an indirect effect of cell division errors. Consistently, kinetochore proteins (normally confined to centromeres in dividing cells) were observed localized in neuronal compartments like axons and synapses in Drosophilapmc.ncbi.nlm.nih.gov. Parallel findings in mammals suggest this is a deeply conserved phenomenon. In cultured rat hippocampal neurons, knockdown of the Mis12 kinetochore protein similarly increased filopodia-like protrusions and altered dendritic spine developmentpmc.ncbi.nlm.nih.gov. A key conclusion from these studies is that kinetochore complexes are “repurposed to sculpt developing synapses and dendrites” in both invertebrates and vertebratespmc.ncbi.nlm.nih.gov. Figure 2 illustrates this concept: core kinetochore components (Mis12, Ndc80, etc.) redistribute to neuronal dendrites, where they restrain excessive neurite branching and promote the maturation of synaptic connectionspmc.ncbi.nlm.nih.gov.

Beyond synapses, kinetochore proteins also guide neuron morphology at the whole-cell level. In Caenorhabditis elegans, the highly conserved KMN network (Knl1–Mis12–Ndc80) was shown to have a crucial cell division-independent role in nervous system wiring

www.molbiolcell.org. Selective degradation of KNL-1 in fully differentiated worm neurons led to disorganized head ganglia and mispatterned axon tracts in the nerve ring (the worm “brain”)www.molbiolcell.org. Strikingly, fine dissection of KNL-1’s domains revealed that the same motifs used to recruit SAC signaling proteins (Bub1/Bub3 and protein phosphatase 1) during mitosis are also required for its neuronal functionwww.molbiolcell.org. In other words, the checkpoint-signaling apparatus of the kinetochore is harnessed to help neurons position their axons correctly. Similarly, a mutation in the Ndc80 microtubule-binding interface (which normally attaches chromosomes to spindle fibers) caused defective axon bundling in the developing nerve ringwww.molbiolcell.org. These genetic manipulations underscore that both the microtubule-binding capacity and signaling activity of the kinetochore complex are redeployed for neuronal morphogenesiswww.molbiolcell.org. It appears that during neurodevelopment, kinetochore proteins act as molecular scaffolds in neurons – organizing the cytoskeleton and perhaps cell adhesion cues to ensure proper neurite fasciculation and placementwww.molbiolcell.org.

Synaptic function and circuit assembly: Anaphase-promoting complex (APC/C) proteins also moonlight at synapses to refine neural circuitry. Several studies in worms, flies, and mammals have converged on a model where post-mitotic neurons use the ubiquitin–proteasome system, traditionally a cell-cycle regulator, to control synaptic growth. In C. elegans, Juo and Kaplan (2004) first showed that APC/C^Cdh1 regulates glutamate receptor abundance at synapses, thereby modulating synaptic strength

pmc.ncbi.nlm.nih.gov. In Drosophila, APC/C was found to restrain synaptic size independently of its role in cell divisionpmc.ncbi.nlm.nih.gov. Mutations in APC/C components (e.g. the APC2 subunit or Fzr/Cdh1 activator, also known as “Cort” in flies) led to overgrown NMJ synapses with increased bouton number, identifying APC/C as a key “brake” on synaptic expansionpmc.ncbi.nlm.nih.gov. Similarly, Yang et al. (2009) demonstrated in mammalian neurons that the Cdc20-APC/C complex directs presynaptic differentiation. In cultured rat neurons and the developing cerebellum, Cdc20-APC/C triggers degradation of NeuroD2, a transcription factor that normally suppresses presynaptic assemblypubmed.ncbi.nlm.nih.gov. By targeting NeuroD2 for destruction, APC/C^Cdc20 allows the activation of NeuroD2’s downstream genes (such as the synaptic protein Complexin-2) and thereby promotes the formation of functional presynaptic terminalspubmed.ncbi.nlm.nih.gov. This elegant mechanism shows how a mitotic ubiquitin ligase is repurposed to control neuron-specific protein turnover: instead of targeting cell-cycle regulators, it targets differentiation factors to drive synapse development. Notably, this pathway operates well after neurons have exited the cell cycle, highlighting that SAC machinery can exert direct control over neuronal maturation.

Finally, an intriguing aspect of kinetochore/SAC protein repurposing in neurons is their role in neuronal stress responses and plasticity. Recent work in Drosophila injury models found that transcripts for kinetochore and SAC proteins are upregulated in neurons after dendrite damage

www.molbiolcell.org. Using targeted RNAi, Tang and Rolls (2020) showed that reducing kinetochore (Mis12 complex), chromosome passenger complex (Aurora B kinase) or SAC components in post-mitotic neurons impaired dendrite regeneration after injurywww.molbiolcell.orgwww.molbiolcell.org. Mechanistically, in uninjured neurons these proteins appear to suppress excessive microtubule growth in dendrites – their depletion led to a surge in microtubule plus-end dynamics specifically in dendrites (but not axons)www.molbiolcell.org. The authors discovered that co-knockdown of γ-tubulin (the microtubule nucleator) could rescue the hyperdynamic microtubules and restore dendrite regrowth when kinetochore/SAC proteins were absentwww.molbiolcell.org. This suggests that kinetochore complexes, possibly via inherited microtubule-organizing functions, normally act to inhibit ectopic microtubule nucleation in dendrites, thereby preserving dendritic stability and the capacity for orderly regrowthwww.molbiolcell.org. While dendrite injury responses are outside typical “development,” this finding reinforces how deeply ingrained these mitotic proteins are in neuronal cell biology – even a mature neuron can redeploy them for structural plasticity and repair.

In summary, multiple lines of evidence across species demonstrate that conserved kinetochore and SAC proteins play novel roles in neurodevelopment. They regulate neural progenitor dynamics, guide neuronal differentiation, and directly sculpt neuronal architecture – from axon pathways to dendritic spines and synapses. These proteins provide a molecular toolkit that developing neurons have evolutionarily hijacked: a kinetochore that once merely tethered chromosomes now tethers and tunes the neuronal cytoskeleton, and a checkpoint that once halted dividing cells now times the delivery of synaptic components. This repurposing is supported by vivid imaging (e.g. kinetochore markers present at synaptic sites

pmc.ncbi.nlm.nih.gov) and robust genetics (neuron-specific knockdowns yielding developmental phenotypes) in systems ranging from C. elegans and Drosophila to mice and human neurons in culture. Such convergence strongly suggests an ancient strategy in which post-mitotic cells, especially neurons, co-opt cell division proteins to drive the extraordinarily complex morphogenesis of the nervous system.

Broader Developmental Functions

Beyond the nervous system, kinetochore and SAC proteins have been implicated in a variety of other developmental contexts. These roles often center on fundamental processes like stem cell lineage regulation, tissue architecture, and organogenesis – processes that, while not neural, similarly require orchestrating cell behavior in time and space.

Stem cell and progenitor differentiation in various tissues: The theme observed in neural stem cells – where cell cycle regulators influence differentiation – appears to be a recurring motif. APC/C^Cdh1, for instance, is broadly utilized as cells exit the cell cycle to differentiate. In mammalian systems, APC/C^Cdh1 is active in many post-mitotic cells and tissues (e.g. adult brain, muscle), where it helps maintain the differentiated state by degrading proliferation-inducing factors

www.pnas.org. In vitro studies have shown APC/C^Cdh1 activity is required for differentiation of embryonic stem cells and various progenitors, including lens fiber cells and myoblastswww.tandfonline.com. In Drosophila muscle development, APC/C^Fzr was reported to promote the proper timing of myoblast fusion and muscle fiber maturation, again by targeting cell-cycle or growth proteins for degradation (paralleling its role in neuroblasts). Thus, an emerging picture is that when a stem or progenitor cell commits to differentiate, it often enlists APC/C^Cdh1 to enforce a one-way decision – permanently exit the cell cycle and progress down the differentiation pathwaywww.frontiersin.orgwww.frontiersin.org. This concept extends to plant development as well (though outside our animal-focused scope): many plant cell differentiation events involve APC/C regulators, underscoring the evolutionary conservation of this strategy.

Tissue morphogenesis and organ formation: Kinetochore proteins, with their potent cytoskeletal interfaces, have been tied to the shaping of tissues and organs. A striking example is the role of CENP-F (also known as mitosin), a large kinetochore protein, in heart development and ciliogenesis. CENP-F is normally a component of the outer kinetochore that helps bind microtubules. In mice, however, cardiac-specific deletion of CENP-F leads to embryonic heart defects, notably impaired ventricular wall trabeculation (the formation of myocardial ridges)

pmc.ncbi.nlm.nih.gov. This appears to stem not only from reduced cardiomyocyte proliferation, but also defective cell migration and adhesion within the developing heart tissuepmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. Indeed, cellular analyses revealed that CENP-F–null fibroblasts have multiple interphase anomalies: they migrate poorly, adhere abnormally, and fail to form primary cilia, all correlating with overly stable microtubulespmc.ncbi.nlm.nih.gov. CENP-F normally binds and destabilizes microtubules (it has two MT-binding domains and can even latch onto depolymerizing tips)pmc.ncbi.nlm.nih.gov. Without CENP-F, microtubules become hyperstabilizedpmc.ncbi.nlm.nih.gov, leading to exaggerated focal adhesions and stalled cell motilitypmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. In the embryonic heart, such changes likely hinder cardiomyocytes from migrating and rearranging properly during chamber maturation, thus causing structural defectspmc.ncbi.nlm.nih.gov. Notably, CENP-F has also been linked to human developmental disorders: mutations in CENP-F are associated with ciliopathy syndromes, consistent with its role in primary cilia formationjmg.bmj.com. These syndromes often present with heart malformations, skeletal abnormalities, and neurodevelopmental issues – a phenotype spectrum reminiscent of other cilia and centriole genes. The CENP-F example highlights how a kinetochore protein has evolved moonlighting functions in interphase: regulating microtubule dynamics, cell polarity, and organelle biogenesis (cilia), which in turn are critical for organ development.

Other developmentally repurposed roles have been noted across species. In C. elegans, the same KMN network that guides neuron axons also influences epidermal morphogenesis: partial loss of kinetochore components was reported to affect the closure of the embryonic epidermis (a process requiring coordinated cell shape changes and migrations). While details are still emerging, one hypothesis is that kinetochore proteins might interact with cortical actin or adhesion complexes during epidermal cell morphogenesis, leveraging their force-bearing properties outside mitosis. Similarly, in Drosophila oogenesis, a few studies hint that spindle checkpoint proteins (like Mad2) may modulate the asymmetric division of oocyte vs. nurse cells, or ensure proper meiotic spindle assembly – blurring the line between a pure “meiotic” role and a developmental one that ensures a viable egg. And in yeast, which lack multicellular development, we interestingly see no such alternative roles – a reminder that these new functions likely emerged in multicellular lineages. For instance, yeast Ndc80 and Mis12 are dedicated solely to chromosome segregation, whereas in worms/flies these same proteins have acquired additional binding partners to impact neuronal structures

www.molbiolcell.org. This comparative insight supports the idea that new developmental functions arose without extensive sequence divergence, but rather by integrating conserved proteins into novel cellular contexts and multi-protein networks present only in multicellular organisms.

Comparative analysis across models: While each organism offers unique examples, common themes can be drawn. In worms, flies, zebrafish, mice, and human organoid models, a recurrent function of repurposed mitotic proteins is to organize the cytoskeleton during developmental events. For neurons, this means guiding microtubule and actin networks for neurite outgrowth; for other cells, it can mean orienting the mitotic spindle in stem cells (thus influencing cell fate) or contributing to cell polarity in epithelia. The KMN kinetochore network emerges as a central player across phyla – in nematodes and insects it shapes neuronal connectivity

www.molbiolcell.org, and we speculate it may have analogous roles in vertebrates (though redundancy often makes it challenging to dissect in mammals). The APC/C complex is another repeatedly recruited module, controlling differentiation timing in contexts as diverse as neurogenesis, lens fiber maturation, and T-cell development. It is fascinating that evolution has again and again tapped these ancient proteins for new purposes. Rather than inventing entirely new machineries, evolution tends to redeploy existing, robust machinery (with perhaps slight modifications) to meet novel challenges of multicellular life. Kinetochore and SAC proteins, given their ability to bind cytoskeleton and mediate protein degradation signals, are ideal “functional building blocks” for such redeployment.

Mechanistic Insights and Evolutionary Perspective

How have these quintessential mitotic proteins been adapted for developmental functions? Several mechanistic principles are beginning to emerge. One theme is modular reuse: different domains of these proteins can serve distinct functions depending on context. Kinetochore proteins often have separable regions for microtubule attachment, protein recruitment, and signaling. In neurons, these modules can be repurposed to interact with non-mitotic structures. For example, the KNL1 protein uses its N-terminal motifs (which recruit SAC components during mitosis) to likely recruit phosphatases and other factors in neurons that organize axon bundling

www.molbiolcell.org. Simultaneously, its C-terminus (which binds the Ndc80 complex and microtubules) helps form physical linkages between microtubules in neighboring axonswww.molbiolcell.org. This dual functionality – a signaling hub and a structural linker – is critical for KNL1’s neuronal role, as mutating either function disrupts nervous system architecturewww.molbiolcell.org. Such findings suggest that evolution didn’t need to invent new protein domains; it simply redeployed existing ones to new cellular locales. Another example is CENP-F: its long coiled-coil structure contains multiple microtubule-binding domains. In dividing cells these help stabilize kinetochore fibers, but in differentiating cells those same domains allow CENP-F to anchor and destabilize interphase microtubules at the cell cortex or ciliary basepmc.ncbi.nlm.nih.gov. Minor biochemical tweaks – e.g. differential phosphorylation or subcellular targeting – could then tailor CENP-F’s activity to interphase needs. Indeed, CENP-F is regulated by distinct kinases in mitosis vs. in interphase (CDK1 vs. GSK3β, respectively, in some studies), illustrating how cell cycle-dependent modification might gate its function to the appropriate context. In neurons (which are permanently in G0), the absence of mitotic phosphorylation may automatically bias CENP-F to its interphase mode, promoting cytoskeletal dynamics necessary for migration and connectivity.

Gene duplication and specialization have also contributed to evolutionary co-option. The presence of two APC/C activators, Cdc20 and Cdh1, is an ancient feature, but in multicellular organisms their roles have diverged: Cdc20 largely drives mitotic transitions, whereas Cdh1 is often expressed in G1 and differentiating cells. Simulations and experimental evolution in yeast indicate that a single APC/C activator cannot optimally fulfill both roles, so the duplication (retained throughout eukaryotes) allowed one activator (Cdh1) to accumulate mutations or regulatory interactions favoring post-mitotic functions. For instance, higher metazoans evolved E3 ubiquitin ligase substrates for APC/C^Cdh1 that are not present in unicells – such as the aforementioned NeuroD2 in neurons

pubmed.ncbi.nlm.nih.gov, or cell cycle inhibitors like p27^Kip1 in differentiating muscle cells. This points to a broader mechanism: new protein–protein interactions underlie much of the co-option. Highly conserved core proteins (like Bub1, Ndc80, CENP-C) likely gained novel binding partners in multicellular contexts. Some of these partners might be tissue-specific adaptors that localize the complex to new sites. For example, a neuron-specific protein might bind Mis12 or Ndc80 and ferry it to synaptic membranes. While the exact adaptors are still unknown, the localization of kinetochore proteins in synapsespmc.ncbi.nlm.nih.govhints at such targeting. It’s also possible that low-level expression of these proteins in differentiated cells went unnoticed by evolution for eons, until complex bodies made it useful – i.e., the proteins were present as “latent” factors that could be recruited into new pathways without drastic genetic change.

From an evolutionary perspective, the reuse of mitotic proteins for development might be driven by the need for coordination between cell division and cell fate decisions. Early embryogenesis requires tight coupling of the cell cycle with developmental patterning; thus, proteins that sat at the interface (like SAC components that sense spindle status and can signal to cytoplasmic factors) were prime candidates to link division with differentiation. Over time, some roles became completely decoupled from division. We see vestiges of this transition in phenomena like neuronal cell cycle re-entry: in some neurodegenerative conditions, neurons aberrantly turn on cell-cycle proteins and then undergo apoptosis. This suggests that normally, neurons keep certain cell-cycle proteins “on standby” for non-dividing functions – but if improperly regulated, those same proteins can trigger cell-cycle processes inappropriately. Evolution has had to balance these outcomes, retaining useful non-mitotic functions while avoiding inadvertent cell division. Mechanistically, this is achieved by tight transcriptional and post-translational control. Many kinetochore/SAC genes are now known to have complex expression patterns – for instance, expressed in stem cells, downregulated during mid-differentiation, then re-expressed in mature cells for specialized functions. The transcription factor E2F, a cell-cycle regulator, also controls expression of some kinetochore genes, and E2F is repurposed in differentiating cells to coordinate cell cycle exit with the upregulation of genes needed for terminal differentiation. Therefore, the evolutionary co-option of mitotic proteins is intertwined with rewiring of cell-cycle gene regulatory networks.

In summary, evolutionary repurposing of kinetochore and SAC proteins proceeded not by reinventing the wheel, but by using the conserved “wheel” in new ways. Structural features (microtubule-binding, protein docking sites, enzymatic activities) encoded in these proteins were adapted through new interactions and regulatory controls. This allowed organisms to leverage robust, pre-existing machinery to meet new developmental demands – such as building a brain or a heart – with relatively minor genetic innovation. It is a testimony to nature’s engineering that the same protein complex can, in one context, prevent aneuploidy in a dividing cell, and in another, guide a growing axon to its target.

Biomedical Relevance

Unraveling the developmental roles of kinetochore and SAC proteins is not only of academic interest but also has important biomedical implications. Many congenital disorders and neurodevelopmental diseases have now been traced to mutations in genes encoding these “cell division” proteins. As mentioned, biallelic mutations in human BUB1 or BUBR1 cause syndromes characterized by microcephaly, developmental delay, and mosaic aneuploidy

pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. These conditions, such as Mosaic Variegated Aneuploidy (MVA) or certain cohesinopathies, underscore how a fault in checkpoint proteins during development can lead to tissue-specific pathologies (e.g. a small brain) presumably due to massive loss of progenitor cells. Interestingly, the severe microcephaly seen in these patients suggests simply preventing aneuploidy (a generic cellular function) is especially crucial in the developing brain – aligning with the idea that neural development has co-opted these proteins and thus is uniquely sensitive to their disruption. In a broader sense, dozens of primary microcephaly genes (MCPH) encode mitotic spindle or centrosome proteinspmc.ncbi.nlm.nih.gov, reinforcing the concept that the expansion of the human cerebral cortex required fine-tuned use of cell-cycle regulators in neuroprogenitors.

Beyond development, misregulation of these proteins in adults can contribute to diseases like cancer and neurodegeneration. Overexpression of kinetochore proteins such as CENP-F, Ndc80, or Bub1 is frequently observed in tumors

pmc.ncbi.nlm.nih.gov, correlating with high proliferative index and chromosomal instability. But intriguingly, it may also affect tumor cell behavior in development-like ways – for instance, CENP-F upregulation in cancers has been linked to increased cell motility and metastasis, possibly recapitulating its role in cell migration during developmentpmc.ncbi.nlm.nih.gov. Thus, the same features that aid in organogenesis can be hijacked by cancer cells for invasion. Conversely, inducing the developmental, non-mitotic functions of checkpoint proteins could have therapeutic potential. For example, forced activation of APC/C^Cdh1 in cancer cells can drive them into differentiation or senescence, halting tumor growth. In the nervous system, understanding these pathways could illuminate new targets for neurodevelopmental disorders. If kinetochore proteins are crucial for synapse formation, might subtle mutations or dysregulation contribute to synaptic dysfunction in autism or intellectual disability? Indeed, there is emerging evidence linking mutations in SAC regulators to neurodevelopmental syndromes beyond microcephaly – for instance, certain cases of developmental delay with epilepsy have been associated with mutations in APC/C co-factors.

Finally, the ability of neurons to reactivate kinetochore/SAC proteins for regeneration (as seen in flies

www.molbiolcell.org) hints at therapeutic angles in regenerative medicine. If we could pharmacologically enhance or mimic these pathways, we might improve neuronal regeneration after injury or in neurodegenerative conditions. Cdh1, for instance, has been explored as a drug target to promote axon regeneration in the spinal cord: inhibiting APC/C^Cdh1 briefly can push mature neurons into a pro-growth state. Caution is warranted, as these manipulations tread a fine line between regeneration and oncogenic reactivation of the cell cycle. Nevertheless, the developmental repurposing of mitotic proteins provides a novel set of molecular targets and biomarkers for diseases. For example, CENP-F levels in the blood have been proposed as a biomarker for heart failure and cancer outcomespmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov– reflecting its role in both heart development and tumor progression.

In conclusion, what began as basic research into a “mitosis-only” complex has broadened into a rich understanding that kinetochore and SAC proteins are integral to the development and maintenance of complex tissues. Ongoing studies in organoids and animal models are poised to further dissect these roles. As we fill in the details – the interactomes, the signaling pathways, the structural basis – we not only satisfy an evolutionary curiosity, but we also open doors to innovative therapies for developmental disorders, cancers, and perhaps even enable coaxing cells to regenerate tissues by tapping into these ancient, repurposed mechanisms.

References: (Selected primary research articles that underpin this review)