Notch signaling: Its essential roles in bone and craniofacial development

Pakvasa, Mikhail; Haravu, Pranav; Boachie-Mensah, Michael; Jones, Alonzo; Coalson, Elam; Liao, Junyi; Zeng, Zongyue; Wu, Di; Qin, Kevin; Wu, Xiaoxing; Luo, Han; Zhang, Jing; Zhang, Meng Meng; He, Fang; Mao, Yukun; Zhang, Yongtao; Niu, Chunping; Wu, Meng; Zhao, Xia; Wang, Hao; Huang, Linjuan; Shi, Deyao; Liu, Qing; Ni, N.; Fu, Kai; Lee, Michael J.; Wolf, Jennifer Moriatis; Athiviraham, Aravind; Ho, Sherwin S.W.; He, Tong‐Chuan; Hynes, Kelly; Strelzow, Jason; Dafrawy, Mostafa H. El; Reid, Russell R.

doi:10.1016/j.gendis.2020.04.006

Cited by 37 publications

(26 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The skull was also thin with fused compact bones in Jag1 Ndr/Ndr mice corroborating another risk factor in this mouse model. These data also further support previous reports for the role of Notch signaling in skeletal development and homeostasis 149 .…”

Section: Discussionsupporting

confidence: 92%

Sex differences and risk factors for bleeding in Alagille syndrome

Hankeová

Hul

Laznovsky

et al. 2021

Preprint

View full text Add to dashboard Cite

Alagille syndrome (ALGS) is generally thought of as a pediatric cholestatic liver disease, but spontaneous bleeds are a major cause of death. Here, we investigated bleeding in patients and a mouse model for ALGS (Jag1Ndr/Ndr mice) and asked whether phenotypes identified in mice could be detected in patients non-invasively. Jag1Ndr/Ndr mice spontaneously bled, exhibiting a thin skull and vascular defects. Vascular abnormalities included artery-vein crossings, tortuous vessels, and capillary breakdown. Furthermore, Jag1Ndr/Ndr arteries had sparse vascular smooth muscle cell coverage, which was further aggravated by hypertension. Retinographs from patients with ALGS, biliary atresia, or CADASIL confirmed tortuous blood vessels and artery-vein crossings in ALGS. We also identified sex-specific differences: fewer major vessels in female Jag1Ndr/Ndr mice, and four-fold more female than male patients with intracranial hemorrhage. In conclusion, dysfunctional Jag1 disrupted vascular growth and homeostasis, with sex-specific differences. The mouse model for Alagille syndrome demonstrated multiple bleeding risk factors and vascular defects that can be identified in patients non-invasively.

show abstract

Section: Discussionsupporting

confidence: 92%

Sex differences and risk factors for bleeding in Alagille syndrome

Hankeová

Hul

Laznovsky

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…To carry out the proof-of-principle experiments on the technical and functional feasibility of the FAMSi system, we chose to construct a series of siRNA vectors that target the BMP9-dependent Smad signaling pathway, as we and others have demonstrated that Smad4 and BMP receptor-specific Smad1/Smad5/Smad8 play an important role in BMP9-induced osteoblastic differentiation of MSCs. 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 …”

Section: Resultsmentioning

confidence: 99%

FAMSi: A Synthetic Biology Approach to the Fast Assembly of Multiplex siRNAs for Silencing Gene Expression in Mammalian Cells

Zeng

et al. 2020

Molecular Therapy - Nucleic Acids

Self Cite

View full text Add to dashboard Cite

RNA interference (RNAi) is mediated by an ∼21-nt double-stranded small interfering RNA (siRNA) and shows great promise in delineating gene functions and in developing therapeutics for human diseases. However, effective gene silencing usually requires the delivery of multiple siRNAs for a given gene, which is often technically challenging and time-consuming. In this study, by exploiting the type IIS restriction endonuclease-based synthetic biology methodology, we developed the fast assembly of multiplex siRNAs (FAMSi) system. In our proof-of-concept experiments, we demonstrated that multiple fragments containing three, four, or five siRNA sites targeting common Smad4 and/or BMPR-specific Smad1, Smad5, and Smad8 required for BMP9 signaling could be assembled efficiently. The constructed multiplex siRNAs effectively knocked down the expression of Smad4 and/or Smad1, Smad5, and Smad8 in mesenchymal stem cells (MSCs), and they inhibited all aspects of BMP9-induced osteogenic differentiation in bone marrow MSCs (BMSCs), including decreased expression of osteogenic regulators/markers, reduced osteogenic marker alkaline phosphatase (ALP) activity, and diminished in vitro matrix mineralization and in vivo ectopic bone formation. Collectively, we demonstrate that the engineered FAMSi system provides a fast-track platform for assembling multiplexed siRNAs in a single vector, and thus it may be a valuable tool to study gene functions or to develop novel siRNA-based therapeutics.

show abstract

“…5 ). Finally, the enriched Delta-Notch Pathway in this module is well-established for its role in craniofacial development [ 112 ]. Based on our findings, it is likely that the genes in the Blue and Purple modules, play modular roles in determining divergent carnivorous trophic morphologies in the Tropheini.…”

Section: Discussionmentioning

confidence: 99%

Gene coexpression networks reveal molecular interactions underlying cichlid jaw modularity

2021

View full text Add to dashboard Cite

Background The oral and pharyngeal jaw of cichlid fishes are a classic example of evolutionary modularity as their functional decoupling boosted trophic diversification and contributed to the success of cichlid adaptive radiations. Most studies until now have focused on the functional, morphological, or genetic aspects of cichlid jaw modularity. Here we extend this concept to include transcriptional modularity by sequencing whole transcriptomes of the two jaws and comparing their gene coexpression networks. Results We show that transcriptional decoupling of gene expression underlies the functional decoupling of cichlid oral and pharyngeal jaw apparatus and the two units are evolving independently in recently diverged cichlid species from Lake Tanganyika. Oral and pharyngeal jaw coexpression networks reflect the common origin of the jaw regulatory program as there is high preservation of gene coexpression modules between the two sets of jaws. However, there is substantial rewiring of genetic architecture within those modules. We define a global jaw coexpression network and highlight jaw-specific and species-specific modules within it. Furthermore, we annotate a comprehensive in silico gene regulatory network linking the Wnt and AHR signalling pathways to jaw morphogenesis and response to environmental cues, respectively. Components of these pathways are significantly differentially expressed between the oral and pharyngeal jaw apparatus. Conclusion This study describes the concerted expression of many genes in cichlid oral and pharyngeal jaw apparatus at the onset of the independent life of cichlid fishes. Our findings suggest that – on the basis of an ancestral gill arch network—transcriptional rewiring may have driven the modular evolution of the oral and pharyngeal jaws, highlighting the evolutionary significance of gene network reuse. The gene coexpression and in silico regulatory networks presented here are intended as resource for future studies on the genetics of vertebrate jaw morphogenesis and trophic adaptation.

show abstract

Notch signaling: Its essential roles in bone and craniofacial development

Cited by 37 publications

References 175 publications

Sex differences and risk factors for bleeding in Alagille syndrome

Sex differences and risk factors for bleeding in Alagille syndrome

FAMSi: A Synthetic Biology Approach to the Fast Assembly of Multiplex siRNAs for Silencing Gene Expression in Mammalian Cells

Gene coexpression networks reveal molecular interactions underlying cichlid jaw modularity

Contact Info

Product

Resources

About