Kindler Syndrome Presenting as Colitis in an Infant.

Kindler syndrome (KS) is an autosomal recessive genodermatosis characterized by skin atrophy, blistering, photosensitivity, and mucosal inflammation. We present a unique case of KS with early and severe neonatal onset in a two-month-old female who presented with severe failure to thrive (FTT) and chronic diarrhea since birth. The infant also had multiple fluid-filled cysts on her foot since birth, which resolved and reappeared at different sites. Anemia, hyponatremia, and coloboma of the right iris were also observed. Whole exome sequencing revealed a homozygous mutation in the FERMT1 gene, confirming the diagnosis of KS. Our case demonstrates a distinct clinical phenotype involving severe colitis and FTT in addition to the typical skin manifestations of KS. This atypical presentation highlights the need for further investigations to gain insights into the impact of the kindlin-1 defect on organs beyond the skin and to explore potential therapeutic approaches for managing severe colitis in affected patients.

FERM domain containing kindlin 1 knockdown attenuates inflammation induced by intracerebral hemorrhage in rats via NLR family pyrin domain containing 3/nuclear factor kappa B pathway.

Intracerebral hemorrhage (ICH) is an incurable neurological disease. Microglia activation and its related inflammation contribute to ICH-associated brain damage. FERM domain containing kindlin 1 (FERMT1) is an integrin-binding protein that participates in microglia-associated inflammation, but its role in ICH is unclear. An ICH model was constructed by injecting 50 µl of autologous blood into the bregma of rats. FERMT1 siRNA was injected into the right ventricle of the rat for knockdown of FERMT1. A significant striatal hematoma was observed in ICH rats. FERMT1 knockdown reduced the water content of brain tissue, alleviated brain hematoma and improved behavioral function in ICH rats. FERMT1 knockdown reduced microglia activity, inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activity and decreased the expression of inflammatory factors including IL-1ß and IL-18 in the peri-hematoma tissues. BV2 microglial cells were transfected with FERMT1 siRNA and incubated with 60 µM Hemin for 24 h. Activation of NLRP3 inflammasome induced by hemin were reduced in microglia when FERMT1 was knocked down, leading to decreased production of inflammatory factors IL-1ß and IL-18. In addition, knockdown of FERMT1 prevented the activation of nuclear factor kappa B (NF-κB) signaling pathway in vivo and in vitro. Our findings suggested that down-regulation of FERMT1 attenuated microglial inflammation and brain damage induced by ICH via NLRP3/NF-κB pathway. FERMT1 is a key regulator of inflammatory damage in rats after ICH.

Effect of c-CBL overexpression on activation of astrocytes in spinal cord of rats with neuropathic pain: relationship with Kindlin-1 / 中华麻醉学杂志

Objective:To evaluate the effect of c-CBL overexpression on activation of astrocytes in the spinal cord of rats with neuropathic pain and the relationship with Kindlin-1.Methods:Eighteen clean-grade healthy male Sprague-Dawley rats, aged 10-12 weeks, weighing 250-280 g, were divided into 3 groups ( n=6 each) using a random number table method: sham operation group (S group), neuropathic pain group (NP group) and c-CBL overexpression group (c-CBL group). The model of neuropathic pain was developed by chronic compression of the sciatic nerve in anesthetized rats.On 1 day before operation, c-CBL overexpression vector 10 μl was intrathecally injected in group c-CBL, while blank vehicle 10 μl was intrathecally injected in S and NP groups.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured on 1 day before operation (T 0) and 1, 4 and 7 days after operation (T 1-3). The rats were sacrificed by decapitation after measurement of the pain threshold at T 3, and the spinal cord of L 4-6 was taken for determination of the expression of Kindlin-1, glial fibrillary acidic protein (GFAP), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) (by Western blot) and co-expression of Kindlin-1 with c-CBL (by co-immunoprecipitation). Results:Compared with group S, the MWT was significantly decreased and TWL was shortened at T 2, 3 in group NP and group c-CBL, the expression of Kindlin-1, GFAP, TNF-α and IL-1β was significantly up-regulated in group NP, and the expression of c-CBL was significantly up-regulated in group c-CBL ( P<0.05). Compared with group NP, the MWT was significantly increased and TWL was prolonged at T 2, 3, the expression of Kindlin-1, GFAP, TNF-α and IL-1β was down-regulated, and the expression of c-CBL was up-regulated in group c-CBL ( P<0.05). The results of co-immunoprecipitation showed that there was a protein interaction and co-expression relationship between Kindlin-1 and c-CBL in group NP, and the co-expression of Kindlin-1 with c-CBL was enhanced in group c-CBL when compared with group NP. Conclusions:The overexpression of c-CBL can inhibit activation of astrocytes by down-regulating the expression of Kindlin-1 in the spinal cord, thus reducing inflammatory responses and relieving neuropathic pain in rats.

Wnt10a/ß-catenin signalling is involved in kindlin-1-mediated astrocyte activation in a chronic construction injury rat model.

The activation of spinal astrocytes and release of neuroinflammatory mediators are important events in neuropathic pain (NP) pathogenesis. In this study, we investigated the role of Wnt10a/ß-catenin signalling in kindlin-1-mediated astrocyte activation using a chronic constriction injury (CCI) NP rat model. Using kindlin-1 overexpression and knockdown plasmids, we assessed hyperalgesia, changes in spinal astrocyte activation and the release of inflammatory mediators in a NP rat model. We also performed coimmunoprecipitation, Western blotting and real-time polymerase chain reaction (PCR) to characterize the underlying mechanisms of kindlin-1 in astrocyte cultures in vitro. Kindlin-1 was significantly upregulated in CCI rats and promoted hyperalgesia. Moreover, we observed increased kindlin-1, Wnt10a and glial fibrillary acidic protein (GFAP; biomarker for astroglial injury) levels and the release of inflammatory mediators in NP rats (p < 0.05). Inhibiting GFAP in vitro led to decreased kindlin-1 levels, prevented astrocyte activation, decreased Wnt10a level and the release of inflammatory mediators (p < 0.05). Coimmunoprecipitation showed that kindlin-1 can interact with Wnt10a. We showed that kindlin-1-mediated astrocyte activation was associated with Wnt10a/ß-catenin signalling and the downstream release of inflammatory mediators in a CCI NP rat model. Our findings provide novel insights into the molecular mechanisms of kindlin-1-mediated astrocyte activation after CCI.

Examination of FERMT1 expression in placental chorionic villi and its role in HTR8-SVneo cell invasion.

Transmembrane integrin receptors mediate cell-extracellular matrix as well as cell-cell adhesion. As placental trophoblast cells undergo differentiation they display changes in integrin expression or switching, but the mechanism(s) of integrin activation that supports this differentiation is still unknown. The Fermitin family of adapter proteins (FERMT 1-3) are integrin activators that mediate integrin-mediated signaling. In this study, we examined the spatiotemporal pattern of expression of FERMT1 in human chorionic villi throughout gestation and its role in HTR8-SVneo substrate adhesion and invasion. Placental villous tissue was obtained from patients undergoing elective terminations at weeks 8-14, as well as from term deliveries at weeks 37-40 and analyzed by immunofluorescence. Additionally, HTR8-SVneo trophoblast cells were transfected with FERMT1-specific siRNA or non-targeting siRNA (control) and used in cell-substrate adhesion as well as invasion assays. FERMT1 was primarily localized to membrane-associated regions at the base or around the periphery of the villous cytotrophoblast and proximal as well as distal cell column trophoblast. FERMT1 was also localized to endothelial cells of blood vessels in chorionic villi. siRNA-mediated depletion of FERMT1 in HTR8-SVneo cells did not markedly alter HTR8-SVneo cell-substrate adhesion but did significantly decrease invasion (P < 0.05) compared to control cells. These novel findings identify the presence of the integrin activator FERMT1 in trophoblast cells and that FERMT1 can regulate HTR8-SVneo cell invasion. FERMT1 may directly influence integrin activation and the subsequent integrin-mediated signaling and differentiation that underlies the acquisition of the invasive trophoblast phenotype in vivo.

Relationship between spinal lncRNA and kindlin-1/Wnt3a signaling pathway in a rat model of neuropathic pain / 中华麻醉学杂志

Objective:To investigate the relationship between spinal long chain noncoding RNA (lncRNA) and kindlin-1/Wnt3a signaling pathway in a rat model of neuropathic pain (NP).Methods:The experiment was performed in two parts.Experiment Ⅰ Sprague-Dawley rats of both sexes, aged 7 days, weighing 15-20 g, were selected.Rats were sacrificed, the dorsal horn of spinal cord was removed, and the primary astrocytes were extracted and cultured.Lipopolysaccharide 1 μg/ml was added to induce the activation of astrocytes for 24 h. The lncRNA binding to kindlin-1 was identified using PCR immunoprecipitation method.The localization of lncRNA FOXF1-AS1 in astrocytes was observed by fluorescence in situ hybridization, and the binding between lncRNA FOXF1-AS1 and kindlin-1 was detected by biotin-labeled magnetic bead method.Experiment Ⅱ Thirty clean-grade healthy male Sprague-Dawley rats, aged 10-12 weeks, weighing 250-280 g, were divided into 5 groups ( n=6 each) using a random number table method: sham operation control group (group C), NP group, lncRNA FOXF1-AS1 overexpression group (group F), lncRNA FOXF1-AS1 overexpression plus kindlin-1 shRNA group (group FK) and lncRNA FOXF1-AS1 overexpression + Wnt inhibitor group (group FW). NP was induced by chronic constrictive injury in anesthetized animals.In group F, lncRNA FOXF1-AS1 overexpression lentivirus 10 μl was intrathecally injected at 28 days before operation, and vector virus 10 μl was intrathecally injected in the other groups.In FK group, kindlin-1 interfering shRNA interference adenovirus 10 μl, and vector virus 10 μl was intrathecally injected in the other groups.In group FW, Wnt inhibitor IWP-2 10 μl was intrathecally injected at 1-3 days after operation, artificial cerebrospinal fluid 10 μl was intrathecally injected at the same time point in the other groups.Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured at 1 day before operation, at 4 days and 7 days after operation.The animals were sacrificed at the end of measurement of pain threshold at 7 days after operation, and the spinal cord tissues were taken for determination of the expression of kindlin-1, Wnt3a and glial fibrillary acidic protein (GFAP) (by Western blot) and the contents of tumor necrosis factor (TNF)-α and interleukin (IL)-1β (IL-1β) (using enzyme-linked immunosorbent assay). Results:ExperimentⅠ lncRNA FOXF1-AS1, which was expressed in the cytoplasm of astrocytes, combined with kindlin-1.Experiment Ⅱ Compared with C group, MWT was significantly decreased, TWL was shortened at 4 and 7 days after operation, the expression of kindlin-1, Wnt3a and GFAP in spinal cord was up-regulated, and the contents of TNF-α and IL-1β were increased in group NP ( P<0.05). Compared with NP group, MWT was significantly decreased, TWL was shortened at 4 and 7 days after operation, the expression of kindlin-1, Wnt3a and GFAP in spinal cord was up-regulated, and the contents of TNF-α and IL-1β were increased in F group, MWT was increased, TWL was prolonged at 4 and 7 days after operation, and the contents of TNF-α and IL-1β were decreased in group FK and group FW, the expression of kindlin-1, Wnt3a and GFAP was down-regulated in group FK, and the expression of kindlin-1 was up-regulated, and expression of Wnt3a and GFAP was down-regulated in group FW ( P<0.05). Compared with group F, MWT was significantly increased, TWL was prolonged at 4 and 7 days after operation, and the contents of TNF-α and IL-1β were decreased in group FK and group FW, the expression of spinal kindlin-1, Wnt3a and GFAP was down-regulated in group FK, and expression of Wnt3a and GFAP was down-regulated in group FW ( P<0.05). Conclusion:lncRNA FOXF1-AS1 can up-regulate kindlin-1 expression, activate Wnt3a signaling pathway, promote astrocyte activation, and then regulate inflammatory responses and is involved in the process of neuropathic pain in rats.

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.

Sharpin suppresses ß1-integrin activation by complexing with the ß1 tail and kindlin-1.

BACKGROUND: Previously sharpin has been identified as an endogenous inhibitor of ß1-integrin activation by directly binding to a conserved region in the cytoplasmic tails (CTs) of the integrin ß1-associated α subunits. METHODS: Here we employed biochemical approaches and cellular analyses to evaluate the function and molecular mechanism of the sharpin-kindlin-1 complex in regulating ß1-integrin activation. RESULTS: In this study, we found that although the inhibition of sharpin on ß1-integrin activation could be confirmed, sharpin had no apparent effect on integrin αIIbß3 activation in CHO cell system. Notably, a direct interaction between sharpin and the integrin ß1 CT was detected, while the interaction of sharpin with the integrin αIIb and the ß3 CTs were substantially weaker. Importantly, sharpin was able to inhibit the talin head domain binding to the integrin ß1 CT, which can mechanistically contribute to inhibiting ß1-integrin activation. Interestingly, we also found that sharpin interacted with kindlin-1, and the interaction between sharpin and the integrin ß1 CT was significantly enhanced when kindlin-1 was present. Consistently, we observed that instead of acting as an activator, kindlin-1 actually suppressed the talin head domain mediated ß1-integrin activation, indicating that kindlin-1 may facilitate recruitment of sharpin to the integrin ß1 CT. CONCLUSION: Taken together, our findings suggest that sharpin may complex with both kindlin-1 and the integrin ß1 CT to restrict the talin head domain binding, thus inhibiting ß1-integrin activation.

Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes.

Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin ß subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.

Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology.

Esophageal cancer (EC) is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry (IHC) and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin-1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.

Kindlin-1 protects cells from oxidative damage through activation of ERK signalling.

Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to ß-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats.

BACKGROUND: Hyperbaric oxygen (HBO) therapy is proven to attenuate neuropathic pain in rodents. The goal of the present study was to determine the potential involvement of the Kindlin-1/Wnt-10a signaling pathway during astrocyte activation and inflammation in a rodent model of neuropathic pain. METHODS: Rats were assigned into sham operation, chronic constriction injury (CCI), and CCI + HBO treatment groups. Neuropathic pain developed in rats following CCI of the sciatic nerve. Rats in the CCI + HBO group received HBO treatment for five consecutive days beginning on postoperative day 1. The mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) tests were performed to determine mechanical and heat hypersensitivity of animals, respectively. Kindlin-1, Wnt-10a and ß-catenin protein expression was examined by immunohistochemistry and Western blot analysis. Expression of tumor necrosis factor (TNF)-α was also determined by ELISA. RESULTS: Our findings demonstrated that HBO treatment significantly suppressed mechanical and thermal hypersensitivity in the CCI neuropathic pain model in rats. HBO therapy significantly reversed the up-regulation of Kindlin-1 in dorsal root ganglia (DRG), spinal cord, and hippocampus of CCI rats. CCI-induced astrocyte activation and increased levels of TNF-α were efficiently reversed by HBO (P < 0.05 vs. CCI). HBO also reversed Wnt-10a up-regulation induced by CCI in the DRG, spinal cord, and hippocampus (P < 0.05 vs. CCI). CONCLUSIONS: Our findings demonstrate that HBO attenuated CCI-induced rat neuropathic pain and inflammatory responses, possibly through regulation of the Kindlin-1/Wnt-10a signaling pathway.

Focal adhesion molecule Kindlin-1 mediates activation of TGF-ß signaling by interacting with TGF-ßRI, SARA and Smad3 in colorectal cancer cells.

Kindlin-1, an integrin-interacting protein, has been implicated in TGF-ß/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-ß/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-ß/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-ß receptor I (TßRI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with TßRI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-ß/Smad3 signaling pathway. Functionally, Kindlin-1 promoted colorectal cancer (CRC) cell proliferation in vitro and tumor growth in vivo, and was also required for CRC cell migration and invasion via an epithelial to mesenchymal transition. Kindlin-1 was found to be increased with the CRC progression from stages I to IV. Importantly, raised expression level of Kindlin-1 correlates with poor outcome in CRC patients. Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TßRI and thereby activates TGF-ß/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-ß/Smad3 signaling and may also be a potential target for CRC therapeutics.

Overexpression of HPV16 E6* Alters ß-Integrin and Mitochondrial Dysfunction Pathways in Cervical Cancer Cells.

BACKGROUND: High-risk human papillomaviruses (HPV) cause nearly all cases of cervical cancer, as well as many types of oral and anogenital cancer. Alternative splicing increases the capacity of the HPV genome to encode the proteins necessary for successful completion of its infectious life cycle. However, the roles of these splice variants, including E6*, the smaller splice isoform of the E6 oncogene, in carcinogenesis are not clear. MATERIALS AND METHODS: SiHa (HPV16(+)) and C33A (HPV(-)) cells were transfected with the E6* plasmid, and tandem mass tag-labeled protein levels were quantified by mass spectrometry. Proteomic analyses identified pathways affected by E6* in both HPV(+) and HPV(-) cells, and pathways were validated using in vitro methods. RESULTS: A total of 4,300 proteins were identified and quantified in lysates of SiHa and C33A cells with and without HPV16 E6* expression. SiHa and C33A cells expressing E6* underwent changes in protein expression affecting integrin signaling and mitochondrial dysfunction pathways, respectively. Subsequent experiments were performed to validate selected E6*-mediated alterations in protein levels. CONCLUSION: E6* modifies the expression of proteins involved in mitochondrial dysfunction and oxidative phosphorylation in C33A cells, and ß-integrin signaling in SiHa cells.

Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord.

UNLABELLED: After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9ß1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a ß1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. SIGNIFICANCE STATEMENT: The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.

Kindlin1 regulates microtubule function to ensure normal mitosis.

Loss of Kindlin 1 (Kin1) results in the skin blistering disorder Kindler Syndrome (KS), whose symptoms also include skin atrophy and reduced keratinocyte proliferation. Kin1 binds to integrins to modulate their activation and more recently it has been shown to regulate mitotic spindles and cell survival in a Plk1-dependent manner. Here we report that short-term Kin1 deletion in mouse skin results in impaired mitosis, which is associated with reduced acetylated tubulin (ac-tub) levels and cell proliferation. In cells, impaired mitosis and reduced ac-tub levels are also accompanied by reduced microtubule stability, all of which are rescued by HDAC6 inhibition. The ability of Kin1 to regulate HDAC6-dependent cellular ac-tub levels is dependent on its phosphorylation by Plk1. Taken together, these data define a novel role for Kin1 in microtubule acetylation and stability and offer a mechanistic insight into how certain KS phenotypes, such as skin atrophy and reduced cell proliferation, arise.

Kindler syndrome in mice and men.

Kindler syndrome (KS) in humans is a severe skin blistering disease associated with inflammation and increased risk of epidermal squamous cell carcinoma (SCC). This disease is known to be caused by loss-of-function mutations in Kindlin-1, a focal adhesion ß-integrin binding protein. Thus far, it has been unclear what specific signaling events occur in KS keratinocytes to promote tumorigenesis, especially since loss of ß-integrins and focal adhesion complexes has been previously shown to prevent or delay tumor formation. In the April issue of Nature Medicine, Rognoni and colleagues generate a transgenic mouse lacking Kindlin-1 in the epidermis to model the key features of KS, and show that Kindlin-1 regulates Wnt and TGFß signaling independent of ß-integrins. These ß1-integrin-independent functions of Kindlin-1 may contribute to the increased SCC risk in KS patients.

Cutaneous and laryngeal squamous cell carcinoma in mixed epidermolysis bullosa, kindler syndrome.

Kindler syndrome is a rare autosomal recessive genodermatosis characterized by trauma-induced acral blisters in infancy and childhood, photosensitivity, and progressive poikiloderma. Other clinical features include chronic erosive gingivitis, dysphagia, esophageal and urethral strictures, ectropion, and an increased risk of mucocutaneous squamous cell carcinoma. We describe a patient with Kindler syndrome associated with squamous cell carcinoma of the skin and larynx. He had squamous cell carcinoma on his left knee with simultaneous unresectable laryngeal carcinoma at the age of 43 years. The squamous cell carcinoma on his knee was excised and the laryngeal carcinoma was treated with radiation therapy. Although pathophysiology of Kindler syndrome and its frequency of association with cancer are still not fully elucidated, we speculate that long-term erosion and regeneration of mucosal and cutaneous surfaces may have induced squamous cell carcinoma on the patient's knee and larynx.