Requirement for Jagged1-Notch2 signaling in patterning the bones of the mouse and human middle ear

Teng, Camilla S; Yen, Hai-Yun; Barske, Lindsey; Smith, Bea; Llamas, Juan; Segil, Neil; Go, John L.; Sanchez‐Lara, Pedro A.; Maxson, Robert E.; Crump, J. Gage

doi:10.1038/s41598-017-02574-7

Cited by 31 publications

(21 citation statements)

References 68 publications

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“…Further characterization of hearing loss in ALGS is necessary to explore the etiology; recurrent otitis media related to underlying craniofacial anomalies have been cited as one possible cause as well as defects of the middle ear bones. (28) These data suggest that tympanometry, at a minimum, should be included as routine surveillance in ALGS.…”

Section: Discussionmentioning

confidence: 93%

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Kamath

Goodrich

et al. 2020

Hepatol Commun

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Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.

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Section: Discussionmentioning

confidence: 93%

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Kamath

Goodrich

et al. 2020

Hepatol Commun

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“…Less is known about upper jaw regulation. Although Jagged-Notch signaling restricts mandibular gene expression in parts of the upper first and second arches, maxillary-derived portions of the upper jaw develop normally in zebrafish and mice with reduced Jagged-Notch signaling (Zuniga et al, 2010, Humphreys et al, 2012, Barske et al, 2016, Teng et al, 2017). Six1 mutant mice show a partial transformation of the posterior end of the maxilla into a mandible-like structure, but this phenotype is attributable to an upstream role for Six1 in limiting Edn1 expression within the dorsal pharyngeal endoderm (Tavares et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

et al. 2018

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The jaw is central to the extensive variety of feeding and predatory behaviors across vertebrates. The bones of the lower but not upper jaw form around an early-developing cartilage template. Whereas Endothelin1 patterns the lower jaw, the factors that specify upper-jaw morphology remain elusive. Here, we identify Nuclear Receptor 2f genes (Nr2fs) as enriched in and required for upper-jaw formation in zebrafish. Combinatorial loss of Nr2fs transforms maxillary components of the upper jaw into lower-jaw-like structures. Conversely, nr2f5 misexpression disrupts lower-jaw development. Genome-wide analyses reveal that Nr2fs repress mandibular gene expression and early chondrogenesis in maxillary precursors. Rescue of lower-jaw defects in endothelin1 mutants by reducing Nr2f dosage further demonstrates that Nr2f expression must be suppressed for normal lower-jaw development. We propose that Nr2fs shape the upper jaw by protecting maxillary progenitors from early chondrogenesis, thus preserving cells for later osteogenesis.

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“…However, these mice are not deaf . In contrast, mice with a deletion of Jag1 or Notch2 limited to neural crest cells have malformed stapes and incus, and have a mild to moderate hearing loss …”

Section: Receptors Relevant To Auditory Systemmentioning

confidence: 99%

Growth factor and receptor malfunctions associated with human genetic deafness

Naz

Friedman

2019

Clinical Genetics

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A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafnesscausing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes. K E Y W O R D SEDN3, EDNRB, hearing, HGF, inner ear defects, JAG, MET, NOTCH

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Requirement for Jagged1-Notch2 signaling in patterning the bones of the mouse and human middle ear

Cited by 31 publications

References 68 publications

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

Growth factor and receptor malfunctions associated with human genetic deafness

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