Congenital Poikiloderma With Traumatic Bulla Fokmation and Progressive Cutaneous Atrophy.

Kindler, Theresa

doi:10.1111/j.1365-2133.1954.tb12598.x

Cited by 187 publications

(122 citation statements)

References 12 publications

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“…Presumably, there is a difference between the two isoforms, in three-dimensional conformation, interaction, or function. Patients lacking functional kindlin-1 suffer from Kindler syndrome, despite having normal kindlin-2 expression (Kindler, 1954;Ussar et al, 2006). In keratinocytes, both kindlin-1 and kindlin-2 colocalize with focal adhesions; but upon calcium-induced differentiation, the colocalization of kindlin-1, but not kindlin-2, is lost (Ussar et al, 2006).…”

Section: Differential Effects Of Kindlin-1 and -2mentioning

confidence: 99%

Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

Tan¹,

Andrews²,

Kwok³

et al. 2012

J. Neurosci.

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Growing and regenerating axons need to interact with the molecules in the extracellular matrix as they traverse through their environment. An important group of receptors that serve this function is the integrin superfamily of cell surface receptors, which are evolutionarily conserved ␣␤ heterodimeric transmembrane proteins. The function of integrins is controlled by regulating the affinity for ligands (also called "integrin activation"). Previous results have shown that CNS inhibitory molecules inactivate axonal integrins, while enhancing integrin activation can promote axon growth from neurons cultured on inhibitory substrates. We tested two related molecules, kindlin-1 and kindlin-2 (Fermitin family members 1 and 2), that can activate ␤1, ␤2, and ␤3 integrins, for their effects on integrin signaling and integrin-mediated axon growth in rat sensory neurons. We determined that kindlin-2, but not kindlin-1, is endogenously expressed in the nervous system. Knocking down kindlin-2 levels in cultured sensory neurons impaired their ability to extend axons, but this was partially rescued by kindlin-1 expression. Overexpression of kindlin-1, but not kindlin-2, in cultured neurons increased axon growth on an inhibitory aggrecan substrate. This was found to be associated with enhanced integrin activation and signaling within the axons. Additionally, in an in vivo rat dorsal root injury model, transduction of dorsal root ganglion neurons to express kindlin-1 promoted axon regeneration across the dorsal root entry zone and into the spinal cord. These animals demonstrated improved recovery of thermal sensation following injury. Our results therefore suggest that kindlin-1 is a potential tool for improving axon regeneration after nervous system lesions.

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Section: Differential Effects Of Kindlin-1 and -2mentioning

confidence: 99%

Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

Tan¹,

Andrews²,

Kwok³

et al. 2012

J. Neurosci.

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“…9,10,17 However, the kindlins cannot compensate for one another; deficiencies of each kindlin in mice and/or humans gives rise to a distinct phenotype. 9,18 Deficiencies of kindlin-1 give rise to similar phenotypes in humans and mice, 19,20 and mutations in the Kindlin-3 gene in humans can give rise to symptoms ranging from bleeding, to frequent infections and osteopetrosis, resulting from an inability to activate integrins on blood and BM cells. 15,16 Kindlin-2 is the most widely distributed kindlin family member.…”

Section: Introductionmentioning

confidence: 99%

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Pluskota

Dowling

Gordon

et al. 2011

Blood

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Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2 ؉/؊ mice. RM1 prostate tumors grown in kindlin-2 ؉/؊ mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2 ؉/؊ mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2 ؉/؊ mice. Vessels in the kindlin-2 ؉/؊ mice were leaky, and BM transplantation from kindlin-2 ؉/؊ to WT mice did not correct this defect. Endothelial cells derived from kindlin-2 ؉/؊ mice had integrin expression levels similar to WT mice but reduced ␣V␤3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin ␣V␤3. IntroductionAlthough endothelial cells (ECs) are the primary cell type that forms blood vessel tubes, other cell types, including BM-derived cells, smooth muscle cells, and pericytes, are all engaged in forming blood-bearing conduits. Growth factor-growth factor receptor interactions are involved in initial recruitment of these cells while other ligand-receptor systems govern migration of the responding cells into angiogenic tissues (reviewed in Folkman 1 ). Among the cellular receptors that specialize in regulating the adhesive and migratory responses of cells during angiogenesis are members of the integrin family. 2 Integrins of the ␤1 and ␤3 subfamilies on ECs have been implicated in angiogenesis in vivo through knockout 3 and inhibitor approaches 4 and integrin ␣V␤3 and ␣5␤1 are targets of antiangiogenic drugs for cancer treatment (reviewed in Avraamides et al 5 ).The regulation of integrin function in angiogenesis as well as many other responses depends on their ability to undergo activation, a rapid transition from a low-to a high-affinity state for recognition of their ligands. Particularly relevant to angiogenesis is the ability of VEGF to activate integrin ␣V␤3 and ␣5␤1 by engaging one of its EC receptors, VEGFR2. 6 Indeed, VEGFR2 and integrin ␣V␤3 can form a physical complex in EC and influence the functions of each other. 6,7 Two sets of cytoskeletal proteins, the talins and the kindlins, bind to the ␤ cytoplasmic tails and are now known to be involved in integrin activation. [8][9][10] Talin has long been known to be critical for integrin activation 11 and more recent studies have sh...

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“…This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes be- Kindler syndrome (KS; OMIM 173650) is a rare autosomal recessive disorder characterized by trauma-induced skin blistering, skin atrophy, and poikiloderma. 1 KS results from pathogenic mutations in the FERMT1 (formerly KIND1 or C20orf42) gene that encodes fermitin family homolog-1 (FFH1) (formerly kindlin-1 or kindlerin), an actin cytoskeleton and focal adhesion-associated molecule. 2,3 FFH1 is mainly expressed in basal keratinocytes.…”

mentioning

confidence: 99%

Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

Lai-Cheong

Parsons

Tanaka

et al. 2009

The American Journal of Pathology

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Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as ␤1 and ␣6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of ␤4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active ␤1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes be- Kindler syndrome (KS; OMIM 173650) is a rare autosomal recessive disorder characterized by trauma-induced skin blistering, skin atrophy, and poikiloderma.1 KS results from pathogenic mutations in the FERMT1 (formerly KIND1 or C20orf42) gene that encodes fermitin family homolog-1 (FFH1) (formerly kindlin-1 or kindlerin), an actin cytoskeleton and focal adhesion-associated molecule.2,3 FFH1 is mainly expressed in basal keratinocytes. [3][4][5][6] In KS, however, there is often a complete absence of FFH1 protein expression, although some variability may occur. 6 Thus far, 37 different loss-of-function FERMT1 mutations have been identified. 7-9 The mechanism by which these pathogenic FERMT1 mutations result in skin atrophy and blistering, however, remains unclear. Indeed, insight from studies on KS skin and FFH1 has been limited. Ultrastructural and immunohistochemical studies on KS skin have revealed a disrupted and reduplicated cutaneous basement membrane, 4,10 -16 and silencing of FFH1 in HaCaT cells results in reduced cell adhesion, proliferation, and spreading. 17 In addition, cultured KS keratinocytes display decreased cell adhesion and proliferation and exhibit multiple cell polarities

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Congenital Poikiloderma With Traumatic Bulla Fokmation and Progressive Cutaneous Atrophy.

Cited by 187 publications

References 12 publications

Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

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