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BMP-dependent cellular dynamics during cranial suture establishment in zebrafish

ABSTRACT: Cranial sutures separate neighboring skull bones and contain skeletal stem cells that drive bone growth. A key question is how osteogenic activity is controlled to promote bone growth while preventing aberrant bone fusions during skull expansion. Here we integrate single-cell transcriptomics, in vivo expression validation, photoconversion-based lineage tracing, and a zebrafish craniosynostosis model to uncover key developmental transitions regulating bone formation during skull expansion. In addition to conservation of meninges and osteoblast lineage cells between zebrafish and mouse, single-cell transcriptomic analysis of the zebrafish skull reveals distinct subpopulations of suture mesenchyme that undergo transcriptomic changes during suture establishment. While lineage tracing with an osteoblast-specific nlsEOS reporter shows that bone formation largely occurs at suture edges, a subset of mesenchyme cells in the mid-suture region upregulate a suite of genes including BMP antagonists (e.g. grem1a) and pro-angiogenic factors. Further, lineage tracing with grem1a:nlsEOS reveals that this mid-suture subpopulation is largely non-osteogenic. In twist1b; tcf12 mutant zebrafish, a model for the coronal synostosis of Saethre-Chotzen Syndrome, reduction of grem1a+ mid-suture cells correlates with misregulated bone formation and reduced blood vessels at the coronal suture. In addition, combinatorial mutation of BMP antagonists enriched in the mid-suture subpopulation results in increased BMP signaling in the suture, misregulated bone formation, and abnormal suture morphology. These data support roles of a subset of mid-suture mesenchyme in locally promoting BMP antagonism that ensures proper suture morphology.

ORGANISM(S): Danio rerio

PROVIDER: GSE223147 | GEO | 2024/07/11

REPOSITORIES: GEO

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Single-cell analysis identifies a key role for Hhip in murine coronal suture development

Project description:Craniofacial development depends on formation and maintenance of sutures between bones of the skull. In sutures, growth occurs at osteogenic fronts along the edge of each bone and suture mesenchyme separates adjacent bones. We performed single-cell RNA-seq analysis of the embryonic, murine coronal suture. Seven populations at E16.5 and nine at E18.5 comprised the suture mesenchyme, osteogenic cells, and associated populations. Expression of Hhip, an inhibitor of hedgehog (HH) signaling, marked a mesenchymal population distinct from other neurocranial sutures. At E18.5, Hhip-/- coronal osteogenic fronts were closely apposed and HH signaling was increased throughout the depleted suture mesenchyme compared to WT, demonstrating that Hhip is required for normal coronal suture development. Tracing of the neonatal Hhip-expressing population showed that descendant cells persisted in the coronal suture and contributed to calvarial bone growth. Our transcriptomic approach provides a rich resource for insight into normal and abnormal development.

2021-06-26 | GSE178899 | GEO

The developing mouse coronal suture at single-cell resolution

Project description:Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. In order to uncover the cellular diversity within sutures, we conducted single-cell transcriptomic and histological analyses of the embryonic murine coronal suture. We identify Erg and Pthlh as early markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. diverse mesenchymal layers at the coronal suture, including multiple distinct meningeal layers below the suture, and ligamentous, ectocranial, and hypodermal layers above the sutureIn the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones and expressing genes implicated in mechanosensation. Mesenchyme in and around the coronal suture is asymmetrically distributed between the frontal and parietal bones, and we identify different states of osteogenic cells extending from the bone fronts into the more mature bone, and a potential signature for sutural stem cellsIn the meningeal layers, we detect a potential chondrogenic periosteal dura population that may be involved in endochondral ossification that closes sutures. Expression of genes mutated in craniosynostosis is spread across diverse cell types, suggesting multiple points at which homeostasis can fail. This single-cell atlas provides a resource to understand the development of the coronal suture, the suture most commonly fused in craniosynostosis.

2021-06-17 | GSE163693 | GEO

scRNAseq of skeletal tissue during zebrafish craniofacial development

Project description:We used scRNAseq to characterize differentiation of cell populations during zebrafish craniofacial development. We focused critical stages during suture formation, and compared wildtype fish to mutants lacking the transcription factor sp7, that display striking abnormalities in skull and suture formation.

2023-11-02 | GSE246579 | GEO

Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGFβ signaling

Project description:The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here we show genetic inhibition of Tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation. In vitro, axons from peripheral afferent neurons derived from DRGs of wild type mice induce MPC proliferation in a spatially-restricted manner via a soluble factor when co-cultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in BMP and TGFβ signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies following direct axonal co-culture with MPCs confirmed alterations in BMP/TGFβ signaling pathway transcripts. Among these, the BMP inhibitor FSTL1 (Follistatin-like 1) replicated key features of the neural-to-bone influence, including mitogenic and anti-osteogenic effects via inhibition of BMP/TGFβ signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.

2021-09-29 | GSE174313 | GEO

The prenatal frontal and parietal bones are distinct organs.

Project description:The skull vault is composed of frontal and parietal bones that are connected by flexible sutures that protect the growing brain. Intramembranous ossification in the prenatal skull vault starts by mid-gestation in the mouse, and sutures must remain flexible for normal growth and development. Therefore, the balance of bone formation and remodeling needs to be precisely controlled because premature ossification in the sutures causes craniosynostosis (CS) to develop. CS has a variable clinical presentation where two frontal bones may be fused together, or a frontal bone may be fused to a parietal bone. While most studies focus on the premature suture ossification, we hypothesized that the process of intramembranous ossification in the frontal and parietal bones contributes to the etiology of CS. By bulk RNASeq we identified 536 unique transcripts between the frontal and parietal compartments.Taken together, we propose that the frontal bone is more active in bone remodeling than the parietal bone, and this control is important for temporal onset of intramembranous ossification in the skull vault.

2023-10-21 | GSE245664 | GEO

Modifiers and Mediators of Craniosynostosis Severity Revealed by Differential Gene Expression

Project description:Severity of craniosynostosis in humans varies widely even in patients with identical genetic mutations, and severity corresponds with morbidity. In this study we compared RNA sequencing data from cranial tissues of a severe form of Crouzon craniosynostosis syndrome (C57BL/6 FGFR2C342Y/+ mice) with those of a less severe form of Crouzon craniosynostosis (BALB/c FGFR2C342Y/+ mice) to identify genetic modifiers that influence craniosynostosis phenotype severity. Comparison of the mice revealed neonatal onset of coronal suture fusion in the form of suture obliteration in C57BL/6 mice (88% incidence, p<.001 between genotypes) in C57BL/6 mice. Coronal suture fusion in the form of point fusions across the suture occurred at approximately 4 weeks after birth, with less severe skull shape abnormalities, in BALB/c mice. Substantially fewer genes were differentially expressed in BALB/c FGFR2+/+ vs. FGFR2C342Y/+ mice (87 out of 15,893 expressed genes) than in C57BL/6 FGFR2C+/+ vs. FGFR2C342Y/+ mice (2,043 out of 19,097 expressed genes). Further investigation of the gene expression data revealed differential expression of coronal suture associated genes, eph/ephrin boundary genes, cell proliferation genes and osteoblast differentiation genes, among others. The most striking pattern in the data was the minimal change in gene expression seen in BALB/c FGFR2+/+ vs. FGFR2C342Y/+ mice. Analysis of protein processing and lysosomal components support the hypothesis that the craniosynostosis phenotype is less severe in BALB/c mice because the mutant FGFR2C342Y protein is not expressed to the same extent as that seen in C57BL/6 mice. Together, these results suggest that a strategy aimed at increasing degradation of the mutant receptor could lead to diminished phenotype severity.

2020-01-15 | GSE143628 | GEO

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (bulk_RNA-seq)

Project description:Purpose: The cranial suture is a fibrous joint, and similar to the growth plates of the skeletal long bone, they serve as the major centers of calvarial vault morphogenesis. Our group’s identification of a skeletal stem cell isolated from the mouse tibial growth plate prompted us to investigate whether these skeletal stem cells are also resident in the mouse cranial sutures and if they govern postnatal suture patency or fusion. Results: We preformed a spatio-temporal profiling of the mouse cranial sutures by flow cytometry, demonstrating a significant decrease in the temporal representation of skeletal stem cells in fusing versus patent sutures. Moreover, canonical Wnt signaling has a significant impact on skeletal stem cells proliferation and thus representation within the suture, dictating fate: fusion or patency. Breeding an Axin2+/-LacZ mouse, with enhanced activation of canonical Wnt signaling to a Twist1+/− mouse, harboring a coronal craniosynostosis enriched the skeletal stem cell pool in coronal sutures, thereby preventing Twist1+/− craniosynostosis. Conclusions: Our findings suggest an imbalance and/or decrease in resident skeletal stem cells within the cranial sutures gives rise to craniosynostosis, however, restoring this representation by enriching skeletal stem cells within the suture can maintain patency.

2020-04-15 | GSE138880 | GEO

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (scRNA-seq)

2020-04-15 | GSE138881 | GEO

Expression data from mouse calvarial suture mesenchymal cells

Project description:Axin2-expressing calvarial suture stem cells can contribute to calvarial development, homeostatic maintenance, repair, and regeneration. We used microarray to examine the gene expression profiles of Axin2-expressing suture stem cells and Axin2-negative cells in suture mesenchyme.

2015-11-11 | GSE74849 | GEO

Single-cell transcriptomic analysis of craniogenesis in control and SOXC-mutant mice

Project description:SOXC genes (i.e., Sox4, Sox11 and Sox12) are important members of the SOX transcription factor family. They are involved in several developmental processes, including skeleton formation. However, their role in intramembranous ossification and, particularly, in skull development has not beed investigated yet. Here, we employed single-cell RNA-seq technology to better understand the roles of the SOXC genes in craniogenesis and how their inactivation could affect this process. We identified the expression of the SOXC genes in several cranial populations, including osteodermal and meningeal progenitors. Removal of the SOXC genes in the cranial mesenchyme with a Prx1Cre transgene showed changes in the proportions of progenitor clusters and deriving populations (dermal, hypodermal, periosteal, suture and bone cells). Mutant progenitors showed the downregulation of genes involved in cytoskeleton organization, cell adhesion and migration, cell proliferation and steorl biosynthesis. As a result, SOXC-mutant fetuses have underdeveloped bones, sutures, dermis and hypodermis, particularly in the apical regions.

2022-06-08 | GSE174716 | GEO

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