Wyetzner, R. | Search bioRxiv

bioRxiv2024

Wnt activation in mature dermal adipocytes leads to lipodystrophy and skin fibrosis via ATGL-dependent lipolysis.

ObjectiveAccumulation of extracellular matrix (ECM) and dermal adipocyte lipodystrophy occurs during skin fibrosis, which compromises the skins flexibility and function. We recently showed that sustained Wnt activation in dermal progenitor cells leads to fibrotic ECM thickening in the dermis and lipodystrophy of dermal white adipose tissue (DWAT). The aim of this study was to test if Wnt/{beta}-catenin signaling in mature dermal adipocytes directly leads to lipodystrophy and impact skin fibrosis. MethodsWe developed a genetically lineage traceable, DWAT specific, inducible and reversible mouse model of Wnt activation (Adipo-{beta}-catistab) in the dorsal skin. We analyzed the DWAT lipid droplet size, cell identity, and affect on ECM accumulation and remodeling in skin fibrosis. Adipocyte triglyceride lipase (ATGL) is the key rate limiting enzyme of the lipolysis pathway, which is a biological process of breaking down triglyceride stores in adipocytes. The Atgl gene was conditionally deleted in mature dermal adipocytes to test the requirement of the lipolysis pathway in the Wnt-induced lipodystrophy (Adipo-{beta}-catistab; Atglfl/fl). ResultsHere, we utilize mouse genetic models with lineage tracing to show that Wnt activation in mature dermal adipocytes is sufficient to induce adipocyte lipodystrophy and fibrotic collagen remodeling. Upon withdrawal of adipocyte-restricted Wnt activation, lipodystrophy and fibrosis were reversed. Mechanistically, we find that Wnt activation stimulates Adipose Triglyceride Lipase (ATGL)-mediated lipolysis pathway. We found Atgl in dermal adipocytes is functionally required for Wnt-induced lipodystrophy in the DWAT and fibrotic remodeling. ConclusionCollectively, this study demonstrates that Wnt activation in dermal adipocytes promotes lipolysis and may be a novel therapeutic avenue for preventing and reversing lipodystrophy and skin fibrosis.

cell biology↗

bioRxiv2023

Apical expansion of calvarial osteoblasts and suture patency is dependent on graded fibronectin cues

The skull roof, or calvaria, is comprised of interlocking plates of bone. Premature suture fusion (craniosynostosis, CS) or persistent fontanelles are common defects in calvarial development. Although some of the genetic causes of these disorders are known, we lack an understanding of the instructions directing the growth and migration of progenitors of these bones, which may affect the suture patency. Here, we identify graded expression of Fibronectin (FN1) protein in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvarial osteoblasts. Syndromic forms of CS exhibit dysregulated FN1 expression, and we find FN1 expression is altered in a mouse CS model as well. Conditional deletion of Fn1 in CM causes diminished frontal bone expansion by altering cell polarity and shape. To address how osteoprogenitors interact with the observed FN1 prepattern, we conditionally ablate Wasl/N-Wasp to disrupt F-actin junctions in migrating cells, impacting lamellipodia and cell-matrix interaction. Neural crest-targeted deletion of Wasl results in a diminished actin network and reduced expansion of frontal bone primordia similar to conditional Fn1 mutants. Interestingly, defective calvaria formation in both the Fn1 and Wasl mutants occurs without a significant change in proliferation, survival, or osteogenesis. Finally, we find that CM-restricted Fn1 deletion leads to premature fusion of coronal sutures. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.

developmental biology↗