Biology subjects

Atit, R.

Publications and source records attributed to Atit, R..

7 recordsLinked to original sources

bioRxiv2025

Lipodystrophy and recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is a salient feature of skin fibrosis, and is followed by accumulation of extracellular matrix (ECM). Lipodystrophy syndromes, often associated with metabolic co-morbidities, are estimated to affect 1 in 20,000 people. We recently showed that fibrosis-associated lipodystrophy is dependent on sustained Wnt signaling, but the mechanism is unclear. Transcriptomic profiling of mature dermal adipocytes in vivo reveal that Wnt activation downregulates the de novo-lipogenesis (DNL) axis enzymes within 48 hours. We found that protein expression of Fatty Acid Synthase (FASN), a key DNL enzyme, is dependent on sustained Wnt activation in vitro and in vivo. In human systemic sclerosis, FASN mRNA is significantly downregulated during two years of disease. Remarkably, pharmacological inhibition of FASN enzyme during reversal from Wnt induced fibrosis impedes recovery of DWAT lipid content as well as ECM accumulation and topography. All together, we demonstrate that acquired lipodystrophy in the context of skin fibrosis is mediated by a new role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis, opening new avenues for therapeutic targets in skin fibrosis.

cell biology↗

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

Mesenchymal Wnts are required for morphogenetic movements of calvarial osteoblasts during apical expansion

Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral for calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. During apical expansion, we found that mouse calvarial primordia have consistent cellular proliferation, density, and survival with complex tissue scale deformations, raising the possibility that morphogenetic movements underlie expansion. Time lapse light sheet imaging of mouse embryos revealed that calvarial progenitors intercalate in 3D to converge supraorbital arch mesenchyme mediolaterally and extend it apically. In contrast, progenitors located further apically exhibited protrusive and crawling activity. CM cells express non-canonical Wnt/Planar Cell Polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand, Wnt5a-/- mutants have less dynamic cell rearrangements, protrusive activity, and a flattened head shape. Loss of cranial mesenchyme-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of OSX+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin cytoskeleton protein along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis and provide tissue level cues for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.

developmental 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↗

bioRxiv2021

Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial development.

Wnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. The Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and Wnt signaling pathways are activated during calvarial osteoblast cell fate selection. Here, we test the hypothesis that ERK signaling is a mediator of Wnt-dependent cell fate decisions in the cranial mesenchyme. First, we show that loss of Erk1/2 in the cranial mesenchyme results in a diminished domain of osteoblast marker expression and increased expression of cartilage fate markers and ectopic cartilage formation in the frontal bone primordia. Second, we show that mesenchyme Wnt/{beta}-catenin signaling and Wntless are required for ERK activation in calvarial osteoblasts. Third, we demonstrate that Wnt and ERK signaling pathways function together to repress Sox9 expression in mouse cranial mesenchyme. Our results demonstrate a link between the Wnt and ERK signaling pathways in regulating lineage selection in a subset of calvarial cells and provide new insights into Wnt-dependent cell fate decisions.

developmental biology↗

bioRxiv2020

Dermal EZH2 simultaneously orchestrates Wnt/β-catenin signaling dependent dermal differentiation and retinoic acid signaling dependent epidermal proliferation during murine skin development

Skin development and patterning is dependent on factors that regulate the stepwise differentiation of dermal fibroblasts concomitant with dermal-epidermal reciprocal signaling, two processes that are poorly understood. Here we show that dermal EZH2, the methyltransferase enzyme of the epigenetic Polycomb Repressive Complex 2 (PRC2), is a new coordinator of both these processes. Dermal EZH2 activity is present during dermal fibroblast differentiation and is required for spatially restricting Wnt/{beta}-catenin signaling to reinforce dermal fibroblast cell fate. Later in development, dermal EZH2 regulates the differentiation to reticular dermal fibroblasts and initiation of secondary hair follicles. Embryos lacking dermal Ezh2 have elevated epidermal proliferation and differentiation that can be rescued by small molecule inhibition of retinoic acid (RA) signaling. Together, our study reveals that dermal EZH2 acts as a rheostat to control the levels of Wnt/{beta}-catenin and RA signaling to impact fibroblast differentiation cell autonomously and epidermal keratinocyte development non-cell autonomously, respectively.

developmental biology↗

bioRxiv2018

Oscillatory cortical forces promote three dimensional cell intercalations that shape the mandibular arch

Multiple vertebrate embryonic structures such as organ primordia are composed of a volume of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show 3D mesenchymal cell intercalations, rather than cell divisions and biophysical tissue properties, are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor, we show that cortical force oscillations promote these intercalations. Genetic loss and gain of function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity with cytoskeletal oscillation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin bias and cytosolic calcium transients, respectively, to ensure appropriate tissue form during growth. Our data support oriented 3D cell neighbour exchange as a conserved mechanism driving volumetric morphogenesis.

developmental biology↗