Biology subjects

Godsel, L. M.

Publications and source records attributed to Godsel, L. M..

5 recordsLinked to original sources

bioRxiv2026

Desmoglein-1 coordinates cell proliferation and actin dynamics to promote epidermal morphogenesis.

Skin development depends on coordinated biochemical and mechanical signaling to form a multilayered epidermal barrier. Our previous work demonstrated that the stratified tissue-specific desmosomal cadherin Desmoglein-1 (Dsg1) promotes epidermal differentiation in human in vitro models. Dsg1 first appears in the developing mouse epidermis around E14, coinciding with a developmental transition in stratification and the onset of terminal differentiation, raising the question of how Dsg1 contributes to epidermal morphogenesis in vivo. We generated a wild-type (WT) single-cell RNA sequencing (scRNA-seq) atlas of murine skin and integrated scRNA-seq data from Dsg1 knockout (Dsg1 KO) embryos spanning E14.5, E15.5, E16.5, and E18.5. Six keratinocyte subpopulations were annotated, including a Transitional subpopulation co-expressing basal and suprabasal markers, positioned between basal and differentiated states. Dsg1 KO epidermis exhibited reduced thickness at E14.5-E15.5, but recovered by E16.5-E18.5, suggesting compensatory adaptation. Differential gene expression analysis revealed enrichment of cell-cycle and actin-associated programs in Dsg1 KO during late development. EdU incorporation and PCNA staining confirmed increased proliferation in superficial layers accompanied by altered actin organization and changed cell morphology. Notably, actin and the Arp2/3 actin nucleation-promoting factor N-WASP exhibited marked changes in distribution during early and late development, respectively. Mechanistically, Dsg1 associates with Nck1, an adaptor linking N-WASP to Arp2/3-dependent actin polymerization. Silencing Nck1 or N-WASP reduced Dsg1-mediated stratification significantly, while a Nck1-binding-deficient Dsg1 mutant failed to rescue stratification in Dsg1-deficient keratinocytes in vitro. Together, these findings identify a Dsg1-Nck1-N-WASP axis linking desmosomal adhesion to cytoskeletal remodeling and support a model in which Dsg1 coordinates cell-cycle, cell morphology, and actin dynamics to drive epidermal morphogenesis.

cell biology↗

bioRxiv2025

Association of RhoGEF Ect2 with Desmoplakin Supports RhoA Activity at Intercellular Junctions: Implications for Carvajal Disease

Desmoplakin (DP) is an essential component of the desmosomal adhesion complex, tethering intermediate filaments to sites of intercellular adhesion to confer mechanical integrity to tissues. As a frequent target for mutation in cardiocutaneous syndromes that vary widely in phenotype, DPs roles as a signaling hub are rapidly emerging. Here, we identify the RhoGEF Ect2 as a previously unappreciated binding partner of the desmosomal protein DP. DP is required for the localization of Ect2 to keratinocyte desmosomes and cardiac intercalated discs in vitro and in vivo, where it maintains active RhoA (Rho-GTP) at the membrane. We demonstrate further that Ect2 activity is supported by PKC in a DP-dependent manner in cardiac myocytes. Finally, a truncated form of DP expressed in patients with Carvajal syndrome associated with severe cardiocutaneous defects is impaired in its ability to bind and localize Ect2 to cell junctions in cardiomyocytes and keratinocytes isolated from patients. Our findings delineate an important relationship between a component of the desmosome and a critical regulator of actin cytoskeletal remodeling that could have widespread implications for understanding cardiac and cutaneous health and disease pathogenesis.

cell biology↗

bioRxiv2022

Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis

BackgroundDarier, Hailey-Hailey, and Grovers diseases are rare non-autoimmune acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. ObjectiveTo better understand the underlying mechanisms leading to disease in these conditions we performed RNA-seq on lesional skin samples from Darier, Hailey-Hailey, and Grovers disease patients. MethodsRNA-seq and bioinformatics analyses were performed on banked paraffin embedded diagnostic samples from each disease. For detailed Methods, please see the Methods section in this articles Online Repository at www.jacionline.org. ResultsThe transcriptomic profiles of Darier, Hailey-Hailey, and Grovers disease were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases, psoriasis and atopic dermatitis. Analysis of enriched pathways showed a shared upregulation in keratinocyte differentiation and Th17 inflammatory pathways, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grovers disease. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in Darier, Hailey-Hailey, and Grovers disease. Further, upstream regulator analysis suggests that a decrease in SRF/MRTF activity may be responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared to normal skin. ConclusionThese findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grovers disease, and identify decreases in actin organization pathways as a unique signature present in these conditions. Key MessagesO_LIDarier Disease, Hailey-Hailey Disease, and Grovers Disease share similar transcriptional profiles suggesting common mechanisms of pathogenesis. C_LIO_LISRF/MRTFA activity is reduced in Darier Disease, Hailey-Hailey Disease and Grovers disease, implicating actin organization in acantholysis. C_LI

genomics↗

bioRxiv2021

Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

Sorting and trafficking transmembrane cargo is essential for tissue development and homeostasis. However, the importance of intracellular trafficking in the development and regeneration of stratified epidermis has not been investigated. Here we identify the interaction between VPS35, an essential component of the retromer endosomal trafficking complex, and the desmosomal cadherin, Desmoglein 1 (Dsg1). Dsg1 is specifically expressed in stratified tissues and when properly localized on the plasma membrane, promotes epidermal stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support keratinocyte stratification and differentiation. The retromer enhancing chaperone, R55 promotes the plasma membrane localization of Dsg1 and a Dsg1 mutant associated with Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome, enhancing the ability of SAM-Dsg1 to promote stratification. Our work provides the first evidence for retromer function in epidermal regeneration and identifies it as a potential therapeutic skin disease target.

cell biology↗

bioRxiv2020

Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1s importance in epidermal integrity is underscored by genetic, autoimmune and bacterial toxin-mediated disorders interfering with Dsg1 function. Dsg1 loss-of-function mutations in humans result not only in skin lesions, but also multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice using CRISPR/Cas9. Whole transcriptome analysis of E18.5 Dsg1-/- skin showed changes consistent with the observed aberrant differentiation and barrier impairment. Comparing epidermal transcriptomes from E18.5 Dsg1-deficient mice and humans with Dsg1 mutations revealed a shared psoriatic-like IL-17-skewed inflammatory signature and less so a pro-allergic IL-4/13 signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from autoimmune anti-Dsg1 pemphigus foliaceus antibodies, transcriptomic analysis of pemphigus skin lesions lacks a prominent IL-17 signature. Thus, beyond impairing the physical barrier, chronic loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, possibly predisposing to skin inflammation.

immunology↗