<i>Fgfr3</i> mutation disrupts chondrogenesis and bone ossification in zebrafish model mimicking CATSHL syndrome partially via enhanced Wnt/β-catenin signaling

Sun, Xianding; Zhang, Ruobin; Chen, Hangang; Du, Xiaolan; Chen, Shuai; Huang, Junlan; Liu, Mi; Xu, Meng; Luo, Fei; Jin, Min; Su, Nan; Qi, Han; Yang, Jing; Tan, Qiaoyan; Zhang, Dali; Ni, Zhenhong; Liang, Sen; Zhang, Bin; Chen, Di; Zhang, Xin; Luo, Lingfei; Xie, Yangli

doi:10.7150/thno.45286

Cited by 29 publications

(28 citation statements)

References 58 publications

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“…Whole-mount in situ hybridization in zebrafish was performed as previous study 67 , 68 . Digoxigenin-labelled antisense RNA probes were produced with a DIG RNA labeling kit (Roche, #11175025910).…”

Section: Methodsmentioning

confidence: 99%

Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development

Guo¹,

Li²,

Liu³

et al. 2021

Theranostics

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Trio is a unique member of the Rho-GEF family that has three catalytic domains and is vital for various cellular processes in both physiological and developmental settings. TRIO mutations in humans are involved in craniofacial abnormalities, in which patients present with mandibular retrusion. However, little is known about the molecular mechanisms of Trio in neural crest cell (NCC)-derived craniofacial development, and there is still a lack of direct evidence to assign a functional role to Trio in NCC-induced craniofacial abnormalities. Methods: In vivo , we used zebrafish and NCC-specific knockout mouse models to investigate the phenotype and dynamics of NCC development in Trio morphants. In vitro , iTRAQ, GST pull-down assays, and proximity ligation assay (PLA) were used to explore the role of Trio and its potential downstream mediators in NCC migration and differentiation. Results: In zebrafish and mouse models, disruption of Trio elicited a migration deficit and impaired the differentiation of NCC derivatives, leading to craniofacial growth deficiency and mandibular retrusion. Moreover, Trio positively regulated Myh9 expression and directly interacted with Myh9 to coregulate downstream cellular signaling in NCCs. We further demonstrated that disruption of Trio or Myh9 inhibited Rac1 and Cdc42 activity, specifically affecting the nuclear export of β-catenin and NCC polarization. Remarkably, craniofacial abnormalities caused by trio deficiency in zebrafish could be partially rescued by the injection of mRNA encoding myh9 , ca-Rac1, or ca-Cdc42. Conclusions: Here, we identified that Trio, interacting mostly with Myh9, acts as a key regulator of NCC migration and differentiation during craniofacial development. Our results indicate that trio morphant zebrafish and Wnt1-cre;Trio fl/fl mice offer potential model systems to facilitate the study of the pathogenic mechanisms of Trio mutations causing craniofacial abnormalities.

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Section: Methodsmentioning

confidence: 99%

Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development

Guo¹,

Li²,

Liu³

et al. 2021

Theranostics

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“…Both early stage osteoblast markers, such as col10a1a , and late-stage osteoblast markers, such as spp1, osn , and col1a2 , exhibit decreased expression. Additionally, upregulation of the chondrogenic proliferation and irregular directional orientation of chondrocytes can be observed in fgfr3 mutant fish, accompanied by an upregulation of Ihh and canonical Wnt signalling [ 3 ]. Thus, fgfr3 downregulates Wnt/ß-catenin and Ihh signalling.…”

Section: Molecular Regulation Of Osteochondrogenesis In the Mandibular And Hyoid Archesmentioning

confidence: 99%

“…Currently, the research of zebrafish craniofacial development is growing in intensity, since the genetic machinery controlling PA development is similar among zebrafish, mice, and humans. Some researchers even use a zebrafish model to study human craniofacial diseases, such as CATSHL syndrome (tall stature and hearing loss) and cleft lip/palate [ 2 , 3 , 4 ]. The adult viscerocranium is composed of many individually distinct elements and requires a coordinated integration of various tissues.…”

Section: Introductionmentioning

confidence: 99%

The Mandibular and Hyoid Arches—From Molecular Patterning to Shaping Bone and Cartilage

Fabik

Psutkova

Machoň

2021

IJMS

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The mandibular and hyoid arches collectively make up the facial skeleton, also known as the viscerocranium. Although all three germ layers come together to assemble the pharyngeal arches, the majority of tissue within viscerocranial skeletal components differentiates from the neural crest. Since nearly one third of all birth defects in humans affect the craniofacial region, it is important to understand how signalling pathways and transcription factors govern the embryogenesis and skeletogenesis of the viscerocranium. This review focuses on mouse and zebrafish models of craniofacial development. We highlight gene regulatory networks directing the patterning and osteochondrogenesis of the mandibular and hyoid arches that are actually conserved among all gnathostomes. The first part of this review describes the anatomy and development of mandibular and hyoid arches in both species. The second part analyses cell signalling and transcription factors that ensure the specificity of individual structures along the anatomical axes. The third part discusses the genes and molecules that control the formation of bone and cartilage within mandibular and hyoid arches and how dysregulation of molecular signalling influences the development of skeletal components of the viscerocranium. In conclusion, we notice that mandibular malformations in humans and mice often co-occur with hyoid malformations and pinpoint the similar molecular machinery controlling the development of mandibular and hyoid arches.

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“…bcl9) , involved in shuttling and retaining β-catenin to the nucleus and driving transcriptional activity of downstream target genes. Abnormal accumulation of nuclear β-catenin in prdm3 mutant chondrocytes at later stages of development further explains the chondrocyte polarity, orientation, intercalation and differentiation defects, as high sustained β-catenin signaling is inhibitory to cartilage differentiation [24, 25, 31, 79]. On the other hand, while prdm16 mutants have these same chondrocyte morphological and differentiation defects, affecting the same signaling pathways, but instead with a dramatic reduction of canonical Wnt/β-catenin signaling and absence of low-level maintenance of nuclear β-catenin that would otherwise help facilitate chondrocyte differentiation and maturation.…”

Section: Resultsmentioning

confidence: 99%

PRDM proteins control Wnt/β-catenin activity to regulate craniofacial chondrocyte differentiation

Shull

Lencer

et al. 2021

Preprint

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Cranial neural crest (NCC)-derived chondrocyte precursors undergo a dynamic differentiation and maturation process to establish a scaffold for subsequent bone formation, alterations in which contribute to congenital birth defects. Here, we demonstrate that transcription factor and histone methyltransferase proteins Prdm3 and Prdm16 control the differentiation switch of cranial NCCs to craniofacial cartilage. Loss of either results in hypoplastic and unorganized chondrocytes due to impaired cellular orientation and polarity. We show that PRDMs regulate cartilage differentiation by controlling the timing of Wnt/β-catenin activity in strikingly different ways: Prdm3 represses while Prdm16 activates global gene expression, though both by regulating Wnt enhanceosome activity and chromatin accessibility. Finally, we show that manipulating Wnt/β-catenin signaling pharmacologically or generating prdm3-/-;prdm16-/- double mutants rescues craniofacial cartilage defects. Our findings reveal upstream regulatory roles for Prdm3 and Prdm16 in cranial NCCs to control Wnt/β-catenin transcriptional activity during chondrocyte differentiation to ensure proper development of the craniofacial skeleton.

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Fgfr3 mutation disrupts chondrogenesis and bone ossification in zebrafish model mimicking CATSHL syndrome partially via enhanced Wnt/β-catenin signaling

Cited by 29 publications

References 58 publications

Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development

Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development

The Mandibular and Hyoid Arches—From Molecular Patterning to Shaping Bone and Cartilage

PRDM proteins control Wnt/β-catenin activity to regulate craniofacial chondrocyte differentiation

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