Gain-of-function variants and overexpression of RUNX2 in patients with nonsyndromic midline craniosynostosis

Cuellar, Araceli; Bala, Krithi; Pietro, Lorena Di; Barba, Marta; Yagnik, Garima; Liu, Jia Lie; Stevens, Christina G.; Hur, David J.; Ingersoll, Roxann; Justice, Cristina M.; Drissi, Hicham; Kim, Jin Oh; Lattanzi, Wanda; Boyadjiev, Simeon A.

doi:10.1016/j.bone.2020.115395

Cited by 20 publications

(19 citation statements)

References 52 publications

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“…S5), alkaline phosphatase staining is significantly diminished in the lower jaw of ncl -/- embryos compared to ncl +/+ embryos. Interestingly, in the neurocranium, osteoblasts in the cranial sutures at both 3 dpf and 5 dpf stain for alkaline phosphatase, which reveals the shape of the sutures in ncl -/- mutant embryos is altered, consistent with the effects of Runx2 mutations in humans 30,31 .…”

Section: Resultssupporting

confidence: 55%

Nucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomalies

Dash

Trainor

2021

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rRNA transcription and ribosome biogenesis are global processes required for growth and proliferation of all cells, yet perturbation of these processes in vertebrates leads to tissue-specific defects termed ribosomopathies. Mutations in rRNA transcription and processing proteins often lead to craniofacial anomalies, however the cellular and molecular reasons for this are poorly understood. Therefore, we examined the function of the most abundant nucleolar phosphoprotein, Nucleolin (Ncl), in vertebrate development. We discovered that Nucleolin is dynamically expressed during embryonic development with high enrichment in the craniofacial tissues. Consistent with this pattern of expression, ncl homozygous mutant (ncl-/-) zebrafish present with craniofacial anomalies such as mandibulofacial hypoplasia. We observe that ncl-/- mutants exhibit decreased rRNA synthesis and p53-dependent neuroepithelial cell death. In addition, the half-life of fgf8a mRNA is reduced in ncl-/- mutants, which perturbs Fgf signaling, resulting in misregulation of Sox9a mediated chondrogenesis and Runx2 mediated osteogenesis. Exogenous addition of human recombinant FGF8 to the mutant zebrafish significantly rescues the cranioskeletal phenotype, suggesting that Nucleolin regulates osteochondroprogenitor differentiation during craniofacial development by post-transcriptionally regulating Fgf signaling. Our work has therefore uncovered a novel tissue-specific function for Nucleolin in rRNA transcription and growth factor signaling during embryonic craniofacial development.

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Section: Resultssupporting

confidence: 55%

Nucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomalies

Dash

Trainor

2021

Preprint

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“…On the other hand, we and other groups previously demonstrated that cells isolated from fused sutures of NCS tend to display a constitutively increased osteogenic activity compared to those isolated from open sutures [ 17 , 31 , 32 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. This differential osteogenic activity was also observed in fused-versus-unfused suture-derived cells of patients diagnosed with Saethre–Chotzen syndrome, an autosomal dominant CS due to TWIST1 loss-of-function mutations [ 52 ].…”

Section: Discussionmentioning

confidence: 80%

“…CS occurs in 85% of cases as an isolated and sporadic (i.e., nonfamilial) disorder, in which the abnormal suture fusion apparently results from a developmental defect that directly targets the affected suture(s), without affecting the rest of the body, being hence classified as nonsyndromic craniosynostosis (NCS). NCS is considered a multifactorial disorder, in which gene-gene and/or gene-environment interaction effects are plausibly involved, although their aetiopathogenesis is still largely unclear [8,[14][15][16][17]. The complex nature of craniosynostosis is reflected by the difficulty in obtaining univocal therapeutic protocols.…”

Section: Introductionmentioning

confidence: 99%

GLI1 and AXIN2 Are Distinctive Markers of Human Calvarial Mesenchymal Stromal Cells in Nonsyndromic Craniosynostosis

Pietro

Barba

Prampolini

et al. 2020

IJMS

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All skeletal bones house osteogenic stem cell niches, in which mesenchymal stromal cells (MSC) provide progenitors for tissue growth and regeneration. They have been widely studied in long bones formed through endochondral ossification. Limited information is available on the composition of the osteogenic niche in flat bones (i.e., skull vault bones) that develop through direct membranous ossification. Craniosynostosis (CS) is a congenital craniofacial defect due to the excessive and premature ossification of skull vault sutures. This study aimed at analysing the expression of GLI1, AXIN2 and THY1 in the context of the human skull vault, using nonsyndromic forms of CS (NCS) as a model to test their functional implication in the aberrant osteogenic process. The expression of selected markers was studied in NCS patients’ calvarial bone specimens, to assess the in vivo location of cells, and in MSC isolated thereof. The marker expression profile was analysed during in vitro osteogenic differentiation to validate the functional implication. Our results show that GLI1 and AXIN2 are expressed in periosteal and endosteal locations within the osteogenic niche of human calvarial bones. Their expression is higher in MSC isolated from calvarial bones than in those isolated from long bones and tends to decrease upon osteogenic commitment and differentiation. In particular, AXIN2 expression was lower in cells isolated from prematurely fused sutures than in those derived from patent sutures of NCS patients. This suggests that AXIN2 could reasonably represent a marker for the stem cell population that undergoes depletion during the premature ossification process occurring in CS.

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“…Some NCS, at least those involving the sagittal suture, are believed to represent multifactorial disorders owing to the interplay between a significant genetic background and environmental risk factors [8]. Different genes have been recently associated with NCS, suggesting possible genotype/phenotype correlations between the mutated genes and the patterns of suture closure [5,7,[9][10][11][12][13][14][15][16][17][18][19]. On this regard, it is worth noting that the presence of gene mutations may affect the neurodevelopmental prognosis in both syndromic and nonsyndromic CS patients [18,20].…”

Section: Craniosynostosis: a Heterogeneous Conditionmentioning

confidence: 99%

“…In particular, our group studied the molecular mechanisms implicated in the overactive osteogenic cascade of mesenchymal stromal cells isolated from calvarial tissues of nonsyndromic CS patients, with idiopathic etiology. By studying this cellular model, we identified functional biomarkers (LMP3, BBS9, RUNX2, AXIN2, and GLI1), to be exploited also in the design of molecular targeted therapeutic approaches aimed at regulating the osteogenic commitment of stem cells in the suture niche [10,12,15,21]. Furthermore, Barreto and coworkers developed a 2D culture system based on cells isolated from nonsyndromic CS patients' sutures, to demonstrate that fused-vs-patent suture cells display differential gene expression profiles underlying different stiffness-mediated responses [188].…”

Section: Cell-based Disease Modelling: From 2d To 3d Culture Systemsmentioning

confidence: 99%

Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosynostosis

et al. 2021

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Craniosynostosis (CS) is the second most prevalent craniofacial congenital malformation due to the premature fusion of skull sutures. CS care requires surgical treatment of variable complexity, aimed at resolving functional and cosmetic defects resulting from the skull growth constrain. Despite significant innovation in the management of CS, morbidity and mortality still exist. Residual cranial defects represent a potential complication and needdedicated management to drive a targeted bone regeneration while modulating suture ossification. To this aim, existing techniques are rapidly evolving and include the implementation of novel biomaterials, 3D printing and additive manufacturing techniques, and advanced therapies based on tissue engineering. This review aims at providing an exhaustive and up-to-date overview of the strategies in use to correct these congenital defects, focusing on the technological advances in the fields of biomaterials and tissue engineering implemented in pediatric surgical skull reconstruction, i.e., biodegradable bone fixation systems, biomimetic scaffolds, drug delivery systems, and cell-based approaches.

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Gain-of-function variants and overexpression of RUNX2 in patients with nonsyndromic midline craniosynostosis

Cited by 20 publications

References 52 publications

Nucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomalies

Nucleolin loss-of-function leads to aberrant FGF signaling and craniofacial anomalies

GLI1 and AXIN2 Are Distinctive Markers of Human Calvarial Mesenchymal Stromal Cells in Nonsyndromic Craniosynostosis

Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosynostosis

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