Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea.
In cochlear development, the Notch signaling pathway is required for both the early prosensory phase and a later lateral inhibition phase. While it is known that Hes genes are important downstream mediators of Notch function in lateral inhibition, it is not known what genes function as mediators of the early prosensory function of Notch. We report that two members of the Hes-related gene family, Hesr1 and Hesr2, are expressed in the developing cochlea at a time and place that makes them excellent candidates as downstream mediators of Notch during prosensory specification. We also show that treatment of cochlear explant cultures at the time of prosensory specification with a small-molecule inhibitor of the Notch pathway mimics the results of conditional Jag1 deletion. This treatment also reduces Hesr1 and Hesr2 expression by as much as 80%. These results support the hypothesis that Hesr1 and Hesr2 are the downstream mediators of the prosensory function of Notch in early cochlear development.
Hayashi
Toshinori
T
Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-HNS, Box 357923, USA.
Kokubo
Hiroki
H
Hartman
Byron H
BH
Ray
Catherine A
CA
Reh
Thomas A
TA
Bermingham-McDonogh
Olivia
O
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003051:Cochlea / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D017353:Gene Deletion; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000166:cytology; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D009924:Organ Culture Techniques; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004151:Dipeptides; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; C120420:Hey1 protein, mouse; C485778:Hey2 protein, mouse; C402588:Heyl protein, mouse; C000606274:Jag1 protein, mouse; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester