Alagille syndrome: Chipping away at the tip of the iceberg

Krantz, Ian D.

doi:10.1002/ajmg.10609

Cited by 9 publications

(4 citation statements)

References 15 publications

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“…There are known links of mutations in the Jag‐1 gene to syndromes with skeletal abnormalities. Jag‐1 mutations are responsible for Alagille syndrome, which is an autosomal dominant disorder that causes multiorgan defects in the eyes, kidneys, heart, and liver and skeletal abnormalities in the spine and skull [64, , , , , , , , –73]. This suggests that Jag‐1 ‐mediated Notch signaling is necessary for many differentiation processes, including events in skeletal formation, and in this study, the inhibition of chondrogenesis by DAPT confirmed other studies suggesting that Notch activation is important in early chondrogenesis.…”

Section: Discussionsupporting

confidence: 86%

Notch Signaling Through Jagged-1 Is Necessary to Initiate Chondrogenesis in Human Bone Marrow Stromal Cells but Must Be Switched off to Complete Chondrogenesis

et al. 2008

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We investigated Notch signaling during chondrogenesis in human bone marrow stromal cells (hMSC) in three-dimensional cell aggregate culture. Expression analysis of Notch pathway genes in 14-day chondrogenic cultures showed that the Notch ligand Jagged-1 (Jag-1) sharply increased in expression, peaking at day 2, and then declined. A Notch target gene, HEY-1, was also expressed, with a temporal profile that closely followed the expression of Jag-1, and this preceded the rise in type II collagen expression that characterized chondrogenesis. We demonstrated that the shut-down in Notch signaling was critical for full chondrogenesis, as adenoviral human Jag-1 transduction of hMSC, which caused continuous elevated expression of Jag-1 and sustained Notch signaling over 14 days, completely blocked chondrogenesis. In these cultures, there was inhibited production of extracellular matrix, and the gene expression of aggrecan and type II collagen were strongly suppressed; this may reflect the retention of a prechondrogenic state. The JAG-1-mediated Notch signaling was also shown to be necessary for chondrogenesis, as N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT) added to cultures on days 0 -14 or just days 0 -5 inhibited chondrogenesis, but DAPT added from day 5 did not. The results thus showed that Jag-1-mediated Notch signaling in hMSC was necessary to initiate chondrogenesis, but it must be switched off for chondrogenesis to proceed. STEM CELLS 2008;26:666 -674 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionsupporting

confidence: 86%

Notch Signaling Through Jagged-1 Is Necessary to Initiate Chondrogenesis in Human Bone Marrow Stromal Cells but Must Be Switched off to Complete Chondrogenesis

et al. 2008

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“…2000; Kamath et al. 2002; Krantz, 2002). Skeletal abnormalities include ‘butterfly vertebrae’, craniofacial abnormalities and a growth retardation phenotype (Kamath et al.…”

Section: Human Bone Marrow Mesenchymal Stem Cells (Hmscs)mentioning

confidence: 99%

Cartilage, SOX9 and Notch signals in chondrogenesis

2006

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Cartilage repair is an ongoing medical challenge. Tissue engineered solutions to this problem rely on the availability of appropriately differentiated cells in sufficient numbers. This review discusses the potential of primary human articular chondrocytes and mesenchymal stem cells to fulfil this role. Chondrocytes have been transduced with a retrovirus containing the transcription factor SOX9, which permits a greatly improved response of the cells to three-dimensional culture systems, growth factor stimulation and hypoxic culture conditions. Human mesenchymal stem cells have been differentiated into chondrocytes using well-established methods, and the Notch signalling pathway has been studied in detail to establish its role during this process. Both approaches offer insights into these in vitro systems that are invaluable to understanding and designing future cartilage regeneration strategies.

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“…Gene mutations responsible for multiple anomaly syndromes are often associated with one of the sentinel defects occurring in isolation. Krantz [2002], compared the identification of Jagged1 as the Alagille syndrome gene to finding the “tip of the iceberg.” The submerged portions of the iceberg represent the clinical disorders and isolated malformations that are also caused by alterations in a given disease gene. In accordance with this paradigm, we hypothesized that there may be children with pulmonic stenosis or HCM who do not have additional features of Noonan syndrome yet have a PTPN11 gene mutation.…”

mentioning

confidence: 99%