title: Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear.
abstract: Notch signalling is well-known to mediate lateral inhibition in inner ear sensory patches, so as to generate a balanced mixture of sensory hair cells and supporting cells. Recently, however, we have found that ectopic Notch activity at an early stage can induce the formation of ectopic sensory patches. This suggests that Notch activity may have two different functions in normal ear development, acting first to promote the formation of the prosensory patches, and then later to regulate hair-cell production within the patches. The Notch ligand Serrate1 (Jag1 in mouse and humans) is expressed in the patches from an early stage and may provide Notch activation during the prosensory phase. Here, we test whether Notch signalling is actually required for prosensory patch development. When we block Notch activation in the chick embryo using the gamma-secretase inhibitor DAPT, we see a complete loss of prosensory epithelial cells in the anterior otocyst, where they are diverted into a neuroblast fate via failure of Delta1-dependent lateral inhibition. The cells of the posterior prosensory patch remain epithelial, but expression of Sox2 and Bmp4 is drastically reduced. Expression of Serrate1 here is initially almost normal, but subsequently regresses. The patches of sensory hair cells that eventually develop are few and small. We suggest that, in normal development, factors other than Notch activity initiate Serrate1 expression. Serrate1, by activating Notch, then drives the expression of Sox2 and Bmp4, as well as expression of the Serrate1 gene itself. The positive feedback maintains Notch activation and thereby preserves and perhaps extends the prosensory state, leading eventually to the development of normal sensory patches.
authors.affiliation: Vertebrate Development Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. n.daudet@ucl.ac.uk
authors.forename: Nicolas
authors.initials: N
authors.lastname: Daudet
authors.forename: Linda
authors.initials: L
authors.lastname: Ariza-McNaughton
authors.forename: Julian
authors.initials: J
authors.lastname: Lewis
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000166:cytology* / Q000196:embryology; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018072:Hair Cells, Auditory, Outer / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055748:SOXB1 Transcription Factors; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D024002:HMGB Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000072099:Serrate-Jagged Proteins; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; C064045:delta protein; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D053829:Amyloid Precursor Protein Secretases