Mei Liu

Kinesin‐12 (Kif15) is a canonical mitotic kinesin that crosslinks parallel microtubules and suppresses microtubule catastrophe. It exists in both dimeric and tetrameric oligomerization states that are regulated by ionic conditions and binding partners. Its persistent expression in postmitotic neurons indicates that this ancestral microtubule‐organizing activity has been repurposed for neuronal functions, yet the dendritic role of Kif15 has remained poorly defined. Here, we review and hypothesize KIF15 acting as a dendritic regulator. We propose that in the dendritic shaft, Kif15 exists predominantly as a tetramer crosslinker to organize the mixed‐polarity antiparallel microtubule array. At the neck of the dendritic spines, perhaps due to the electrical signals, the compartmental ion concentration has changed. The dimeric Kif15 transports PSD95 along microtubule plus ends that invade dendritic spines and unloads PSD95 at the postsynaptic sites. There, synaptic activity triggers Ca ²⁺ influx and CaMKII activation to promote Kif15 association with Myosin IIb (Myh10), forming a Kif15‐Myh10 hetero‐complex, which reorganizes the microtubule–actin network to facilitate mushroom‐like dendritic spine formation. This framework explains why Kif15 loss impairs spine complexity, synaptic development, and mood‐related behaviors without causing catastrophic disassembly of dendritic microtubules. It further links KIF15 mutations to cognitive disorders and suggests that mechanistic insights from a mitotic motor to its synaptic functions.

Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive neuronal loss that leads to cognitive, motor, and behavioral impairment. With population aging, NDDs impose an expanding medical and socioeconomic burden, yet most available treatments remain symptomatic rather than disease modifying. Disease mechanisms are increasingly understood as multicellular processes involving neurons, astrocytes, microglia, and other cell types, which complicates target selection and limits translation from conventional models. Intranasal administration offers a noninvasive route for delivering therapeutics to the central nervous system by leveraging olfactory and trigeminal pathways and reducing dependence on blood-brain barrier penetration. This review summarizes recent advances in intranasal strategies for NDDs across diverse therapeutic classes, including peptides and proteins, small molecules and metabolic modulators, nucleic acid-based cargos, and nanocarrier enabled formulations designed to improve retention, stability, and brain deposition. We further highlight emerging organelle centered and bioengineered approaches, such as mitochondrial delivery and other cell organelle or organelle derived systems, alongside cell-based and cell-free biologics including stem cells, secretomes, and extracellular vesicles that provide multi target neuroprotective and immunomodulatory effects. Finally, we discuss key translational challenges, including limited delivery efficiency due to mucociliary clearance, uncertainty in dosing regimens, manufacturing and quality control for complex biologics and organelles, and the need for robust biomarkers and imaging readouts to confirm central target engagement. Collectively, these advances position intranasal delivery as a versatile but evolving platform for next generation interventions in NDDs.

Our understanding of the intrinsic mechanisms that drive the regeneration of damaged axons after a spinal cord injury is still limited. Microtubules are core components of the eukaryotic cytoskeleton and are essential for axonal growth, in part because their stability is governed by post‐translational modifications in mature neurons. Glucose‐dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are expressed in multiple extra‐pancreatic tissues, suggesting biological functions beyond classical endocrine signaling; however, their roles in neuronal cytoskeletal regulation are not well defined. Here, we investigated the effects of GIP in cultured cortical neurons. GIP enhanced microtubule stability and increased the number of axons crossing an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Mechanistically, GIP promoted microtubule acetylation via α‐tubulin N‐acetyltransferase 1 (αTAT1), the major acetyltransferase for α‐tubulin, by suppressing αTAT1 ubiquitination and thereby reducing its proteasomal degradation in inhibitory environments. Although the upstream mechanism remains to be determined, this study provides the first evidence that GIP/GIPR signaling modulates microtubule dynamics, highlighting a potential strategy to re‐activate neuronal growth machinery after injury.

The Wnt/FGF20 axis establishes an organizing center that is largely non-proliferative in the distal blastema during epimorphic regeneration across multiple model systems. However, the underlying mechanisms remain poorly characterized. In this study, we investigate the role of the Wnt/FGF20 axis during tail regeneration in Gekko japonicus. We also developed an in vitro system to evaluate the effects of Wnt agonists, FGF20, and FGFR4 on cultured blastema cells. Our results demonstrate that Wnt signaling is activated in distal blastema cells and contributes to a lower proportion of proliferative cells beneath the epidermal basal layer in the regenerating tail of Gekko japonicus. This Wnt-mediated suppression of proliferation is associated with reduced FGFR4 expression, as confirmed both in vitro and in vivo. Furthermore, Wnt pathway activation upregulates FGF20 expression in distal blastema cells, which promotes the migration of proximal blastema cells without affecting their proliferation. Our findings provide an insight into the organizing center of regenerated tissue, revealing a reciprocal regulatory interaction between the epidermis and blastema cells during successful epimorphic regeneration.

The harmony of neuronal excitation and inhibition is essential for precise neuronal circuitry in the developmental brain, and thus affects the human emotion. Abnormalities of synaptic morphology directly affect neuronal function and contribute to a variety of psychiatric disorders. Previous studies have shown that Kif15 (Kinesin-12), a microtubule-associated motor protein, affects neurite growth, navigation, and branching during neuronal development, revealing the potential of Kif15 to influence neuronal dendritic morphology. A GWAS study in a European population showed that there were variants in both exons and introns of the KIF15 gene on chromosome 3 in patients with depression. Therefore, we generated Kif15^-/- mice using CRISPR/Cas9 technology. In this study, we found that Kif15^-/- mice have exhibited significant impacts on dendritic morphology and function, which contributes to mood disorders. Compared with Kif15 wild-type mice, adolescent Kif15^-/- mice showed a significant decrease in the excitatory postsynaptic scaffolding protein PSD95 and NMDA receptors, as well as a reduction in the total density of dendritic spines and the density of mushroom spines, and a decrease in the frequency of mEPSCs. Meanwhile, the inhibitory postsynaptic scaffold protein Gephyrin and GABRB1 significantly upregulated. However, the adult Kif15^-/- mice simultaneously exhibited an obvious manic behavior and their PSD95 expression increased rapidly, even more than that of the Kif15 wild-type mice. Meanwhile, overexpression of Kif15 in kif15^−/− zebrafish rescued their depressive behavior. In terms of molecular mechanism, we showed that KIF15 interacted with PSD95 protein using both endogenous and exogenous Co-IP assays. Furthermore, we found that PSD95 in Kif15^-/- mice was distributed around neuronal nuclei, in contrast to PSD95 localized close to the cell membrane in Kif15 wild-type mice. In conclusion, our study has identified a microtubule-associated molecular motor, KIF15, that plays a novel role in bipolar disorder through its contributions to spine morphology and function.