Erf Affects Commitment and Differentiation of Osteoprogenitor Cells in Cranial Sutures via the Retinoic Acid Pathway

Vogiatzi, Angeliki; Baltsavia, Ismini; Dialynas, Emmanuel; Théodorou, Vassiliki; Zhou, Yan; Deligianni, Elena; Iliopoulos, Ioannis; Wilkie, Andrew; Twigg, Stephen R. F.; Mavrothalassitis, George

doi:10.1128/mcb.00149-21

Cited by 7 publications

(10 citation statements)

References 92 publications

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“…Although the PF suture in Erf loxP/+ mice at this stage was still well-detected, it displayed closures and deformities in the majority of Erf loxP/− mice. Interrogation of single-cell RNA sequencing data from coronal [24] and frontal [25] sutures for the correlation of Erf expression with other genes, as previously described [22], indicated the mediation of additional pathways in the frontal suture, notably involving signaling and motility (Supplementary Figure S1). To evaluate possible qualitative differences in the ossification of cranial sutures, we utilized Raman spectroscopy on mouse calvaria at P65.…”

Section: Erf Insufficiency In Mice Is Associated With Both Craniosyno...supporting

confidence: 59%

“…In contrast, its absence can affect the differentiation of multiple cell types and can cause malignant transformation [16][17][18][19][20][21]. Recently, we showed that Erf is required for the efficient commitment of suture-derived mesenchymal stem/progenitor cells toward the osteogenic lineage via the retinoic acid (RA) pathway [22]. As RA acts as a morphogen and is reported to have a role in bone development, precise control of ERF nuclear levels and transcriptional effects appear to be important for multiple cellular fates.…”

Section: Introductionmentioning

confidence: 99%

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Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration

Vogiatzi

Keklikoglou

Makris

et al. 2023

IJMS

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ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.

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Section: Erf Insufficiency In Mice Is Associated With Both Craniosyno...supporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration

Vogiatzi

Keklikoglou

Makris

et al. 2023

IJMS

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“…59 Recently, Erf was shown to affect the osteogenic differentiation of cranial suture mesenchymal stem/progenitor cells through retinoic acid (RA) pathway regulation. 60 as these genes contain Ets binding sites 63,64 and Erf might act as transactivator in some settings, as suggested by the down-regulation of genes with Erf chromatin binding after Erf deactivation. 65 ThPOK has not been reported as an ETS transcription target.…”

Section: Discussionmentioning

confidence: 99%

“…Direct transcriptional regulation would also be possible in response to fluctuation in Erk activity, observed during thymocyte maturation 59 . Recently, Erf was shown to affect the osteogenic differentiation of cranial suture mesenchymal stem/progenitor cells through retinoic acid (RA) pathway regulation 60 . RA receptor transcriptional activity was previously shown to increase in DP thymocytes and in SP cells during lineage commitment, 61 whereas the addition of RA in murine fetal thymic organ cultures was shown to drive an increase in CD4 + SP thymocytes, 62 indicating a role of RA pathway in the regulation of T cell maturation.…”

Section: Discussionmentioning

confidence: 99%

ETS2 repressor factor (ERF) is involved in T lymphocyte maturation acting as regulator of thymocyte lineage commitment

Tsiomita

Liveri

Vardaka

et al. 2022

Journal of Leukocyte Biology

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Thymocyte differentiation and lineage commitment is regulated by an extensive network of transcription factors and signaling molecules among which Erk plays a central role. However, Erk effectors as well as the molecular mechanisms underlying this network are not well understood. Erf is a ubiquitously expressed transcriptional repressor regulated by Erk‐dependent phosphorylation. Here, we investigated the role of Erf in T cell maturation and lineage commitment, using a double‐fluorescent Erf‐floxed mouse to produce thymus‐specific Erf knockouts. We observed significant accumulation of thymocytes in the CD4/CD8 DP stage, followed by a significant reduction in CD4SP cells, a trend for lower CD8SP cell frequency, and an elevated percentage of γδ expressing thymocytes in Erf‐deficient mice. Also, an elevated number of CD69+TCRβ+ cells indicates that thymocytes undergoing positive selection accumulate at this stage. The expression of transcription factors Gata3, ThPOK, and Socs1 that promote CD4+ cell commitment was significantly decreased in Erf‐deficient mice. These findings suggest that Erf is involved in T cell maturation, acting as a positive regulator during CD4 and eventually CD8 lineage commitment, while negatively regulates the production of γδ T cells. In addition, Erf‐deficient mice displayed decreased percentages of CD4+ and CD8+ splenocytes and elevated levels of IL‐4 indicating that Erf may have an additional role in the homeostasis, differentiation, and immunologic response of helper and cytotoxic T cells in the periphery. Overall, our results show, for the first time, Erf's involvement in T cell biology suggesting that Erf acts as a potential regulator during thymocyte maturation and thymocyte lineage commitment, in γδ T cell generation, as well as in Th cell differentiation.

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“…5c). For example, Module 3 consisted hypertrophic chondrocytes and chondrocytes cluster, containing common regulons of ERF 49 , FOXC1 50 and ATF2 51 which were reported to participate in the bone formation and osteogenic differentiation. Module 10 was composed of hypertrophic chondrocytes and osteoblasts, containing common regulons of SOX8 52 and ESRRA 53 which were essential regulators for chondrogenic and osteoblast differentiation (Fig.…”

Section: Discussionmentioning

confidence: 99%

The cell developmental atlas of human embryonic temporomandibular joint

Zhu

Tan

Wang

et al. 2022

Preprint

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Background: The temporomandibular joint (TMJ) is a complex joint consisting of the mandibular condyle, temporal articular surface, and articular disc. The functions of mastication, swallowing and articulation are accomplished by the movements of the TMJ. To date, the TMJ has been studied more extensively, but the study of the TMJ is limited by the type of TMJ cells, their differentiation, and their interrelationship during growth and development is unclear. The aim of this study is to establish a molecular cellular developmental atlas of the human TMJ by single-cell RNA sequencing, which will contribute to understanding and solving. Results: We performed a comprehensive transcriptome analysis of TMJ tissue from 3- and 4-month-old human embryos using single-cell RNA sequencing. A total of 15,624 cells were captured and the gene expression profiles of 15 cell populations in human TMJ were determined, including 14 known cell types and a previously unknown cell type named "transition state cells (TSCs)". Immunofluorescence assays confirmed that TSCs are not the same cell cluster as mesenchymal stem cells (MSCs). Pseudotime trajectory and RNA velocity analysis showed that MSCs transformed into TSCs, and TSCs further differentiated into tenocytes, hypertrophic chondrocytes and osteoblasts. In addition, chondrocytes were detected only in 4-month-old human embryonic TMJ. Conclusions: Our study provides an atlas of the earlier cellular development of human embryonic TMJ tissue, which will contribute to a deeper understanding of the pathophysiology of TMJ tissue during repair and ultimately help to solve clinical problems.

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Erf Affects Commitment and Differentiation of Osteoprogenitor Cells in Cranial Sutures via the Retinoic Acid Pathway

Cited by 7 publications

References 92 publications

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration

ETS2 repressor factor (ERF) is involved in T lymphocyte maturation acting as regulator of thymocyte lineage commitment

The cell developmental atlas of human embryonic temporomandibular joint

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