α-parvin is required for epidermal morphogenesis, hair follicle development and basal keratinocyte polarity

Altstätter, Johannes; Hess, Michael W.; Costell, Mercedes; Montañez, Eloi

doi:10.1371/journal.pone.0230380

Cited by 9 publications

(8 citation statements)

References 24 publications

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“…This switch of IAC classes functionally translated into impaired cellular adhesion, indicating a defect in efficient mechanical linkage between IACs and the cytoskeleton (Figure 7). Although prior studies have observed that the sole deletion of PARVA already resulted in impaired cellular adhesion, altered cytoskeletal architecture, and adhesion site formation, 32 , 63 compensatory upregulation of PARVB in podocytes largely prevented any overt cellular dysfunction. In fact, a counterbalancing regulation of Parvin proteins has been previously demonstrated 70 …”

Section: Discussionmentioning

confidence: 78%

“…To test the relevance of PARVA in podocytes, we used a recently established conditional allele for Parva 32 , 63 . We crossed the podocyte-specific hNPHS2-Cre line with a floxed allele for Parva and validated KO efficiency in situ (Figure 2, A and B).…”

Section: Resultsmentioning

confidence: 99%

“…To test the relevance of PARVA in podocytes, we used a recently established conditional allele for Parva. 32,63 We crossed the podocyte-specific hNPHS2-Cre line with a floxed allele for Parva and validated KO efficiency in situ (Figure 2, A and B). Interestingly, podocyte-specific KO did not affect glomerular morphogenesis, reflected by normal glomerular filtration barrier function until the age of 8-10 weeks.…”

Section: Loss Of Parva Results In a Fsgs-like Glomerular Disease With...mentioning

confidence: 99%

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α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier

Rogg¹,

Maier²,

Wymersch³

et al. 2022

JASN

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BackgroundThe cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney’s filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive.MethodsWe mapped the in vivo composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene (Parva) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes in vivo, we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated PARVA single knockout podocytes and PARVA and PARVB double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns.ResultsWe found that PARVA is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of in vitro and in vivo models, we identified an inherent PARVB-dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of PARVA and PARVB induces a switch in structure and composition of integrin adhesion complexes. This redistribution of these complexes translates into a loss of the ventral actin cytoskeleton, decreased adhesion capacity, impaired mechanical resistance, and dysfunctional extracellular matrix assembly.ConclusionsThe findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease.

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Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Loss Of Parva Results In a Fsgs-like Glomerular Disease With...mentioning

confidence: 99%

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α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier

Rogg¹,

Maier²,

Wymersch³

et al. 2022

JASN

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“…Previous studies have revealed that adhesion signals are important factors in HF and AGA development. For example, α-parvin, which is a FA protein that couples integrins to actin cytoskeleton, is indispensable to HF development (Altstaetter et al, 2020 ). Furthermore, there is cross-talk between FA/integrin and Wnt signaling pathways, which is one of the most important signaling pathways in AGA (Ridgway et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Zyxin and Its Potential Function in Androgenetic Alopecia

Liu

Shi

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Androgenetic alopecia (AGA) is the most common progressive form of hair loss, occurring in more than half of men aged > 50 years. Hair follicle (HF) miniaturization is a feature of AGA, and dermal papillae (DP) play key roles in hair growth and regeneration by regulating follicular cell activity. Previous studies have revealed that adhesion signals are important factors in AGA development. Zyxin (ZYX) is an actin-interacting protein that is essential for cell adhesion and migration. The aim of this research was to investigate the expression and potential role of ZYX in AGA. Real-time polymerase chain reaction (RT-PCR) analysis revealed that ZYX expression was elevated in the affected frontal HF of individuals with AGA compared to unaffected occipital HF. Moreover, increased ZYX expression was also observed within DP using immunofluorescence staining. Our in vivo results revealed that ZYX knockout mice showed enhanced hair growth and anagen entry compared to wild-type mice. Reducing ZYX expression in ex vivo cultured HFs by siRNA resulted in the enhanced hair shaft production, delayed hair follicle catagen entry, increased the proliferation of dermal papilla cells (DPCs), and upregulated expression of stem cell-related proteins. These results were further validated in cultured DPCs in vitro. To further reveal the mechanism by which ZYX contributes to AGA, RNA-seq analysis was conducted to identify gene signatures upon ZYX siRNA treatment in cultured hair follicles. Multiple pathways, including focal adhesion and HIF-1 signaling pathways, were found to be involved. Collectively, we discovered the elevated expression of ZYX in the affected frontal hair follicles of AGA patients and revealed the effects of ZYX downregulation on in vivo mice, ex vivo hair follicles, and in vitro DPC. These findings suggest that ZYX plays important roles in the pathogenesis of AGA and stem cell properties of DPC and may potentially be used as a therapeutic target in AGA.

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“…Previous studies have revealed that adhesion signals are important factors in HF and AGA development. For example, α-parvin, which is a FA protein that couples integrins to actin cytoskeleton, is indispensable to HF development (Altstaetter et al, 2020). Furthermore, there is cross-talk between FA/integrin and Wnt signaling pathways, which is one of the most important signaling pathways in AGA (Ridgway et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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α-parvin is required for epidermal morphogenesis, hair follicle development and basal keratinocyte polarity

Cited by 9 publications

References 24 publications

α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier

α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier

Increased Expression of Zyxin and Its Potential Function in Androgenetic Alopecia

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