The CEP170B-KIF2A complex destabilizes microtubule minus ends to generate polarized microtubule network.

Microtubule (MT) minus ends are stabilized by CAMSAP family proteins at noncentrosomal MT-organizing centers. Despite progress in identifying diverse positive regulators, knowledge on the negative regulation of the MT minus-end distribution is lacking. Here, we identify CEP170B as a MT minus-end-binding protein that colocalizes with the microtubule-stabilizing complex at the cortical patches. CEP170B depends on the scaffold protein liprin-α1 for its cortical targeting and requires liprin-α1-bound PP2A phosphatase for its MT localization. CEP170B excludes CAMSAPs-stabilized MT minus ends from the cell periphery in HeLa cells and the basal cortex in human epithelial cells and is required for directional vesicle trafficking and cyst formation in 3D culture. Reconstitution experiments demonstrate that CEP170B autonomously tracks growing MT minus ends and blocks minus-end growth. Furthermore, CEP170B in a complex with the kinesin KIF2A acts as a potent MT minus-end depolymerase capable of antagonizing the stabilizing effect of CAMSAPs. Our study uncovers an antagonistic mechanism for controlling the spatial distribution of MT minus ends, which contributes to the establishment of polarized MT network and cell polarity.

Roles of developmentally regulated KIF2A alternative isoforms in cortical neuron migration and differentiation.

KIF2A is a kinesin motor protein with essential roles in neural progenitor division and axonal pruning during brain development. However, how different KIF2A alternative isoforms function during development of the cerebral cortex is not known. Here, we focus on three Kif2a isoforms expressed in the developing cortex. We show that Kif2a is essential for dendritic arborization in mice and that the functions of all three isoforms are sufficient for this process. Interestingly, only two of the isoforms can sustain radial migration of cortical neurons; a third isoform, lacking a key N-terminal region, is ineffective. By proximity-based interactome mapping for individual isoforms, we identify previously known KIF2A interactors, proteins localized to the mitotic spindle poles and, unexpectedly, also translation factors, ribonucleoproteins and proteins that are targeted to organelles, prominently to the mitochondria. In addition, we show that a KIF2A mutation, which causes brain malformations in humans, has extensive changes to its proximity-based interactome, with depletion of mitochondrial proteins identified in the wild-type KIF2A interactome. Our data raises new insights about the importance of alternative splice variants during brain development.

Cytomorphological Disparities in Invasive Breast Cancer Cells following Neoadjuvant Endocrine Therapy and Chemotherapy.

INTRODUCTION: Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE. METHODS: Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9). RESULTS: In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. After treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NET group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups. CONCLUSION: Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny.

By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.

Circular RNA circ_IRAK3 contributes to tumor growth through upregulating KIF2A via adsorbing miR-603 in breast cancer.

BACKGROUND: Breast cancer (BC) threatens the health of women around the world. Researchers have proved that hsa_circ_0005505 (circ_IRAK3) facilitates BC cell invasion and migration, but the regulatory mechanisms of circ_IRAK3 in BC remain mostly unknown. We aim to explore a new mechanism by which circ_IRAK3 promotes BC progression. METHODS: Levels of circ_IRAK3, microRNA (miR)-603, and kinesin family member 2A (KIF2A) mRNA in BC tissues and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The cell cycle progression, colony formation, and proliferation of BC cells were evaluated by flow cytometry, plate clone, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays. The migration, invasion, and apoptosis of BC cells were determined by transwell or flow cytometry assays. Several protein levels were detected using western blotting. The targeting relationship between circ_IRAK3 or KIF2A and miR-603 was verified via dual-luciferase reporter assay. The role of circ_IRAK3 in vivo was verified by xenograft assay. RESULTS: We observed higher levels of circ_IRAK3 in BC tissues and cell lines than their respective controls. Functional experiments presented that circ_IRAK3 silencing induced BC cell apoptosis, curbed cell proliferation, migration, and invasion in vitro, and decreased tumor growth in vivo. Mechanistically, circ_IRAK3 could modulate kinesin family member 2A (KIF2A) expression through acting as a microRNA (miR)-603 sponge. miR-603 silencing impaired the effects of circ_IRAK3 inhibition on the malignant behaviors of BC cells. Also, the repressive effects of miR-603 mimic on the malignant behaviors of BC cells were weakened by KIF2A overexpression. CONCLUSIONS: circ_IRAK3 exerted a promoting effect on BC progression by modulating the miR-603/KIF2A axis, providing a piece of novel evidence for circ_IRAK3 as a therapeutic target for BC.

Reciprocal regulation of Aurora kinase A and ATIP3 in the control of metaphase spindle length.

Maintaining the integrity of the mitotic spindle in metaphase is essential to ensure normal cell division. We show here that depletion of microtubule-associated protein ATIP3 reduces metaphase spindle length. Mass spectrometry analyses identified the microtubule minus-end depolymerizing kinesin Kif2A as an ATIP3 binding protein. We show that ATIP3 controls metaphase spindle length by interacting with Kif2A and its partner Dda3 in an Aurora kinase A-dependent manner. In the absence of ATIP3, Kif2A and Dda3 accumulate at spindle poles, which is consistent with reduced poleward microtubule flux and shortening of the spindle. ATIP3 silencing also limits Aurora A localization to the poles. Transfection of GFP-Aurora A, but not kinase-dead mutant, rescues the phenotype, indicating that ATIP3 maintains Aurora A activity on the poles to control Kif2A targeting and spindle size. Collectively, these data emphasize the pivotal role of Aurora kinase A and its mutual regulation with ATIP3 in controlling spindle length.

Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation.

The MRE11-RAD50-NBS1 (MRN) complex is well known for participating in DNA damage response pathways in all phases of cell cycle. Here, we show that MRN constitutes a mitosis-specific complex, named mMRN, with a protein, MMAP. MMAP directly interacts with MRE11 and is required for optimal stability of the MRN complex during mitosis. MMAP colocalizes with MRN in mitotic spindles, and MMAP-deficient cells display abnormal spindle dynamics and chromosome segregation similar to MRN-deficient cells. Mechanistically, both MMAP and MRE11 are hyperphosphorylated by the mitotic kinase, PLK1; and the phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase, KIF2A, leading to spindle turnover and chromosome segregation. Our study identifies a mitosis-specific version of the MRN complex that acts in the PLK1-KIF2A signaling cascade to regulate spindle dynamics and chromosome distribution.

High neuropilin and tolloid-like 1 expression associated with metastasis and poor survival in epithelial ovarian cancer via regulation of actin cytoskeleton.

Abnormal expression of neuropilin and tolloid-like 1 (NETO1) has been detected in some human carcinomas. However, the expression of NETO1 and the underlying mechanism in epithelial ovarian cancer (EOC) remain unknown. In this study, we found that a higher NETO1 expression in EOC tissue samples compared to normal ovarian tissue samples was significantly correlated with worse overall survival. Additionally, Cox regression analysis suggested that NETO 1 was independently associated with overall survival. NETO1 overexpression enhanced the EOC cells' migration and invasion capability in vitro via regulation of actin cytoskeleton. Mechanistically, silencing NETO1 reduced the expression of ß-tubulin, F-actin and KIF2A. In conclusion, our results demonstrated the critical role of NETO1 in EOC invasion, and therapies aimed at inhibiting its expression or activity might significantly control EOC growth, invasion and metastatic dissemination.

DDA3 and Mdp3 modulate Kif2a recruitment onto the mitotic spindle to control minus-end spindle dynamics.

Active turnover of spindle microtubules (MTs) for the formation of a bi-orientated spindle, chromosome congression and proper chromosome segregation is regulated by MT depolymerases such as the kinesin-13 family and the plus-end-tracking proteins (+TIPs). However, the control mechanisms underlying the spindle MT dynamics that are responsible for poleward flux at the minus end of MTs are poorly understood. Here, we show that Mdp3 (also known as MAP7D3) forms a complex with DDA3 (also known as PSRC1) and controls spindle dynamics at the minus end of MTs by inhibiting DDA3-mediated Kif2a recruitment to the spindle. Aberrant Kif2a activity at the minus end of spindle MTs in Mdp3-depleted cells decreased spindle stability and resulted in unaligned chromosomes in metaphase, lagging chromosomes in anaphase, and chromosome bridges in telophase and cytokinesis. Although they play opposing roles in minus-end MT dynamics, acting as an MT destabilizer and an MT stabilizer, respectively, DDA3 and Mdp3 did not affect the localization of each other. Thus, the DDA3 complex orchestrates MT dynamics at the MT minus end by fine-tuning the recruitment of Kif2a to regulate minus-end MT dynamics and poleward MT flux at the mitotic spindle.

Overexpression of KIF2A is Suppressed by miR-206 and Associated with Poor Prognosis in Ovarian Cancer.

BACKGROUND/AIMS: This study aimed to investigate the expression and prognostic value of kinesin family member 2A (KIF2A) and the suppression effects of microRNA-206 (miR-206) on KIF2A in ovarian cancer. METHODS: Ovarian cancer tissues from patients and ovarian cancer cell lines (A2780 and SKOV3) were used in this study. miR-206 mimics and control were transiently transfected into cells. RT-qPCR was performed to detect KIF2A mRNA and miR-206 expression levels, Western blot was performed to detect KIF2A protein levels, Dual-Luciferase Reporter Assay was used to examine the inhibition effects of miR-206 on KIF2A mRNA, immunohistochemical staining was used to examine the expression of KIF2A in tissue sections. CCK-8, transwell and Annexin-V-FITC/Propidium Iodide staining with flow cytometry were used to detect the cell proliferation, migration/invasion, and apoptosis respectively. RESULTS: Our study explored the expression profiles of KIF2A and miR-206 in the patients with ovarian cancer. We found that overexpression of KIF2A was associated with a poor prognosis in ovarian cancer. We also found that KIF2A mRNA contains two target sites for miR-206 binding and confirmed that miR-206 directly suppresses KIF2A; inhibits ovarian cancer cell proliferation, migration, and invasion; and induces apoptosis. CONCLUSION: The results suggest KIF2A could serve a valuable prognostic indicator in ovarian cancer and provide a rationale for treatment of ovarian cancer by targeting KIF2A via miR-206.

Down-regulation of KIF2A inhibits gastric cancer cell invasion via suppressing MT1-MMP.

Gastric cancer accounts for a sizeable proportion of global cancer mortality with high morbidity and poor prognosis. Kinesin superfamily proteins (KIFs) are microtubule-dependent motor proteins that function as oncogenes in cancer cells, it has been discovered in recent years. Kinesin family member 2a (KIF2A), a member of the KIFs, has received attention for its role in carcinogenesis and its prognostic value in several human cancers such as breast cancer, colorectal cancer, and squamous cell carcinoma. However, the role of KIF2A in human gastric cancer remains unknown. In this study we aimed to explore the expression and biological functions of KIF2A in human gastric cancer cells, as well as to reveal its potential action mechanism. First, we found that KIF2A was markedly increased in gastric cancer cells (MKN-28, MKN-45, NCI-N87 and SGC-7901) compared to normal gastric mucosa epithelial cells (GES-1). Then KIF2A was successfully silenced in MKN-45 and SGC-7901 cells to facilitate further research into its function. We discovered that KIF2A silencing can significantly inhibit the growth and invasion of MKN-45 and SGC-7901 cells in a time-independent manner, accompanying a decreased expression of Membrane type 1-matrix metalloproteinase (MT1-MMP). When MT1-MMP was reintroduced into MKN-45 and SGC-7901 cells in the KIF2A-siRNA group, only invasion inhibition effects on MKN-45 and SGC-7901 cells induced by KIF2A silencing can be reversed. In conclusion, our study reveals that down-regulation of KIF2A can inhibit gastric cancer cell invasion by suppressing MT1-MMP.

Direct Functional Interaction of the Kinesin-13 Family Member Kinesin-like Protein 2A (Kif2A) and Arf GAP with GTP-binding Protein-like, Ankyrin Repeats and PH Domains1 (AGAP1).

The molecular basis for control of the cytoskeleton by the Arf GTPase-activating protein AGAP1 has not been characterized. AGAP1 is composed of G-protein-like (GLD), pleckstrin homology (PH), Arf GAP, and ankyrin repeat domains. Kif2A was identified in screens for proteins that bind to AGAP1. The GLD and PH domains of AGAP1 bound the motor domain of Kif2A. Kif2A increased GAP activity of AGAP1, and a protein composed of the GLD and PH domains of AGAP1 increased ATPase activity of Kif2A. Knockdown (KD) of Kif2A or AGAP1 slowed cell migration and accelerated cell spreading. The effect of Kif2A KD on spreading could be rescued by expression of Kif2A-GFP or FLAG-AGAP1, but not by Kif2C-GFP. The effect of AGAP1 KD could be rescued by FLAG-AGAP1, but not by an AGAP1 mutant that did not bind Kif2A efficiently, ArfGAP1-HA or Kif2A-GFP. Taken together, the results support the hypothesis that the Kif2A·AGAP1 complex contributes to control of cytoskeleton remodeling involved in cell movement.

Recurrent KIF2A mutations are responsible for classic lissencephaly.

Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to -5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that KIF2A mutations represent significant causes of classic lissencephaly with microcephaly.

High KIF2A expression predicts unfavorable prognosis in diffuse large B cell lymphoma.

Kinesin family member 2A (KIF2A), a conserved motor protein, plays a critical role in the pathogenesis and prognosis of several malignant tumors. The aim of the present study was to investigate KIF2A expression in diffuse large B cell lymphoma (DLBCL), evaluate the association between KIF2A expression and the clinical parameters of the disease, and determine its prognostic value. KIF2A expression was evaluated in 134 DLBCL and 57 reactive hyperplasia samples using immunohistochemistry on a tissue microarray. The correlations between KIF2A expression with clinical parameters and prognosis were estimated using univariate and multivariate analyses. The expression of KIF2A was significantly higher in DLBCL tissue samples compared with those from subjects with reactive hyperplasia (P=0.002). Furthermore, increased expression of KIF2A protein in DLBCL was related to Ann Arbor stage (P=0.027) and international prognostic index (IPI) score (P=0.01). The survival analysis showed that KIF2A expression (P=0.016), serum LDH level (P=0.049), and IPI score (P<0.001) were independent prognostic markers for DLBCL. Our findings also confirmed that downregulating KIF2A expression decreased tumor cell viability, accompanied by downregulation of pAKT levels. Taken together, these data provide the first evidence that increased KIF2A expression predicts poor prognosis in patients with DLBCL, and a rationale for treatment of DLBCL by targeting KIF2A.

[The expression and significance of microtubule - driven protein KIF2A in epithelial ovarian cancer].

Objective: To investigate the protein and mRNA expression of KIF2A in ovarian cancer, and to investigate the migration and invasion ability changes in ovarian cancer cell line HO-8910 transfected by KIF2A-siRNA. Methods: Immunohistochemical method was used to detect the expression of KIF2A in 30 cases of ovarian cancer and 20 cases of ovarian normal tissues. The expression of KIF2A mRNA was detected by RT-PCR. The mRNA and protein expression of KIF2A in cell line HO-8910 was detected by RT-PCR and Western blot after transfected by KIF2A-siRNA in vitro. After the transfection, the cell migration and invasion ability were observed by scratch test and transwell experiments. Result: The expression of KIF2A mRNA and protein in HO-8910 was significantly lower than that in normal ovarian tissue (P<0.05). The capacities of migration and invasion of HO-8910 was suppressed notably after the knockdown of KIF2A (P<0.05). Conclusion: KIF2A gene expression was increased in ovarian cancer, and knockdown of KIF2A gene can inhibit the migration and invasion of ovarian cancer cells. It suggested that KIF2A gene may be a new target for the development of ovarian cancer.

Ska1 cooperates with DDA3 for spindle dynamics and spindle attachment to kinetochore.

Spindle microtubules (MTs) capture kinetochores (KTs) on the centromere sequence of sister chromatids to align at the mitotic equator and segregate toward spindle poles during mitosis. For efficient chromosome capture, KTs initially attach to the lateral surface of a MT, providing a considerably larger contact surface than the MT tip. A sequential change of KT composition upon spindle attachment enables a conversion from lateral to stable end-on attachment. However, the molecular link between spindle dynamics and KT composition is not fully understood. Here, we report that Ska1 and DDA3 act as molecular linkers in the interplay between KTs and spindle dynamics. After recruitment of Kif2a onto the mitotic spindle by DDA3, Ska1 targets Kif2a to the minus-end of spindle MTs and facilitates spindle dynamics. Furthermore, DDA3 targets Ska1 to KTs to stabilize end-on attachment. Thus, our findings identified a definite regulatory mechanism of the search and capture process for stable spindle attachment through cross-talk between spindle dynamics and KT composition mediated by DDA3 and Ska1.

KIF2A overexpression and its association with clinicopathologic characteristics and unfavorable prognosis in colorectal cancer.

Kinesin superfamily protein 2A (KIF2A), an M type nonmotile microtubule depolymerase, has received attention for its role in carcinogenesis and prognostic value in several types of cancer. In this study, we evaluated the expression of KIF2A and its potential and robustness to predict clinical outcomes in colorectal cancer (CRC) patients. The messenger RNA (mRNA) expression of KIF2A was determined in 20 pairs of cancerous and adjacent nontumor tissues by real-time polymerase chain reaction. KIF2A immunohistochemistry was performed on tissue microarray (TMA), composed of 182 CRC and 179 matched adjacent nontumor tissues from surgery, 23 chronic colitis, 43 low-grade, and 18 high-grade intraepithelial neoplasias acquired through intestinal endoscopic biopsy. Univariate and multivariate Cox regression models were used to perform survival analyses. Both KIF2A mRNA and protein product exhibited CRC tissue-preferred expression, when compared with benign tissues. The high KIF2A expression was significantly correlated to TNM stage (P = 0.046) and tumor status (T) (P = 0.007). In univariate and multivariate analyses, high KIF2A expression showed a major prognostic value regarding 5-year survival. The influences of KIF2A expression on the survival were further proven by Kaplan-Meier survival analysis. This study demonstrated CRC tissue-preferred expression pattern of the KIF2A and suggested that high KIF2A expression might serve as an independent maker for poor prognosis in CRC patients.

KIF2A Upregulates PI3K/AKT Signaling through Polo-like Kinase 1 (PLK1) to Affect the Proliferation and Apoptosis Levels of Eriocheir sinensis Spermatogenic Cells.

E. sinensis is an animal model for studying the reproduction and development of crustaceans. In this study, we knocked down the Es-Kif2a gene by injecting dsRNA into E. sinensis and inhibited Es-Plk1 gene expression by injecting PLK1 inhibitor BI6727 into E. sinensis. Then, the cell proliferation level, apoptosis level, and PI3K/AKT signaling expression level were detected. Our results showed that the proliferation level of spermatogenic cells decreased, while the apoptosis level increased after Es-Kif2a knockdown or Es-Plk1 inhibition. In order to verify whether these changes are caused by regulating the PI3K/AKT pathway, we detected the expression of PI3K and AKT proteins after Es-Kif2a knockdown or Es-Plk1 inhibition. Western Blot showed that in both the Es-Kif2a knockdown group and the Es-Plk1 inhibition group, the expression of PI3K and AKT proteins decreased. In addition, immunofluorescence showed that Es-KIF2A and Es-PLK1 proteins were co-localized during E. sinensis spermatogenesis. To further explore the upstream and downstream relationship between Es-KIF2A and Es-PLK1, we detected the expression level of Es-PLK1 after Es-Kif2a knockdown as well as the expression level of Es-KIF2A after Es-Plk1 inhibition. Western Blot showed that the expression of Es-PLK1 decreased after Es-Kif2a knockdown, while there was no significant change of Es-KIF2A after Es-Plk1 inhibition, indicating that Es-PLK1 may be a downstream factor of Es-KIF2A. Taken together, these results suggest that Es-KIF2A upregulates the PI3K/AKT signaling pathway through Es-PLK1 during the spermatogenesis of E. sinensis, thereby affecting the proliferation and apoptosis levels of spermatogenic cells.

Kinesin family member 2A gates nociception.

Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.