Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates

Basch, Martín L.; Brown, Rogers M.; Jen, Hsin I.; Semerci, Fatih; Depreux, Frederic; Edlund, Renée K.; Zhang, Hongyuan; Norton, Christine R.; Gridley, Thomas; Cole, Susan E.; Doetzlhofer, Angelika; Maletić-Savatić, Mirjana; Segil, Neil; Groves, Andrew K.

doi:10.7554/elife.19921

Cited by 78 publications

(82 citation statements)

References 98 publications

(173 reference statements)

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“…Sensory organ development shows similar dose-sensitivity to other Notch-regulated processes, wherein a carefully titrated, moderate reduction of Notch signaling activity mediated by the glycosyltransferases lunatic fringe (Lfng) and manic fringe (Mfng) creates a border between the prosensory primordium of the cochlear domain and the Kölliker's organ. This occurs prior to the fate decision of the first differentiating inner hair cells and their associated supporting cells, affirming the sensitivity of this organ to even very mild changes in Notch signaling intensity (Basch et al, 2016). It is also worth noting that truncated posterior semicircular canals and missing ampullae are observed in Jag1 del1/+ and Foxg1…”

Section: Notch2 and Jag1 Function In The Liversupporting

confidence: 57%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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Section: Notch2 and Jag1 Function In The Liversupporting

confidence: 57%

The developmental biology of genetic Notch disorders

2017

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“…By E13.5, the Sox2+ floor of the cochlear duct undergoes refinement to reveal two new internal boundaries that delineate three subdomains from medial‐to‐lateral: the inner sulcus, the prosensory domain, and the outer sulcus . These are indicated schematically in Figures and (dimensions not drawn to scale).…”

Section: Transcription Factors Expressed On the Floor Of The Cochlearmentioning

confidence: 99%

“…In addition to its effects on lateral induction and/or maintenance of a prosensory fate and lateral inhibition of a hair cell fate, Notch signaling is also required for an even more subtle patterning feature: the precise location of the medial boundary of the organ of Corti within the margin of error of two cell diameters. In this context, Notch acts through the Fringe enzymes, Lfng and Mfng . Fringe enzymes are beta1,3‐N‐acetylglucosaminyltransferases that modify the O‐fucosylated EGF repeats on the Notch receptor .…”

Section: Grns Related To Notch Signalingmentioning

confidence: 99%

The acquisition of positional information across the radial axis of the cochlea

Munnamalai

Fekete

2019

Developmental Dynamics

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The mammalian cochlea detects sound and transmits this information to the brain. A cross section through the cochlea reveals functionally distinct epithelial domains arrayed around the circumference of a fluid‐filled duct. Six major domains include two on the roof of the duct (Reissner's membrane medially and the stria vascularis laterally) and four across the floor of the duct, including the medial and lateral halves of the sensory domain, the organ of Corti. These radial domains are distinguishable in the embryonic cochlea by differential expression of transcription factors, and we focus here on a subset of the factors that can influence cochlear fates. We then move upstream of these genes to identify which of five signaling pathways (Notch, Fgf, Wnt, Bmp, and Shh) controls their spatial patterns of expression. We link the signaling pathways to their downstream genes, separating them by their radial position, to create putative gene regulatory networks (GRNs) from two time points, before and during the time when six radial compartments arise. These GRNs offer a framework for understanding the acquisition of positional information across the radial axis of the cochlea, and to guide therapeutic approaches to repair or regenerate distinct cochlear components that may contribute to hearing loss.

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“…17 Juxtacrine signals mediated by NOTCH pathways establish the sensory epithelium, including hair cells and supporting cells. 18 In humans, WNT 19 and BMP 20 family members are required for development of the auditory system. 21…”

Section: Growth Factors Relevant To the 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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Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates

Cited by 78 publications

References 98 publications

The developmental biology of genetic Notch disorders

The developmental biology of genetic Notch disorders

The acquisition of positional information across the radial axis of the cochlea

Growth factor and receptor malfunctions associated with human genetic deafness

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