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

Author:

Basch Martin L1,Brown Rogers M2,Jen Hsin-I2,Semerci Fatih2,Depreux Frederic3,Edlund Renée K2,Zhang Hongyuan1,Norton Christine R4,Gridley Thomas4,Cole Susan E5,Doetzlhofer Angelika6,Maletic-Savatic Mirjana1278,Segil Neil9,Groves Andrew K1210ORCID

Affiliation:

1. Department of Neuroscience, Baylor College of Medicine, Houston, United States

2. Program in Developmental Biology, Baylor College of Medicine, Houston, United States

3. Department of Cell Biology and Anatomy, Rosalind Franklin University of Medicine and Science, Chicago, United States

4. Maine Medical Center Research Institute, Scarborough, United States

5. Department of Molecular Genetics, The Ohio State University, Columbus, United States

6. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, United States

7. Department of Pediatrics, Baylor College of Medicine, Houston, United States

8. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States

9. Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States

10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States

Abstract

The signals that induce the organ of Corti and define its boundaries in the cochlea are poorly understood. We show that two Notch modifiers, Lfng and Mfng, are transiently expressed precisely at the neural boundary of the organ of Corti. Cre-Lox fate mapping shows this region gives rise to inner hair cells and their associated inner phalangeal cells. Mutation of Lfng and Mfng disrupts this boundary, producing unexpected duplications of inner hair cells and inner phalangeal cells. This phenotype is mimicked by other mouse mutants or pharmacological treatments that lower but not abolish Notch signaling. However, strong disruption of Notch signaling causes a very different result, generating many ectopic hair cells at the expense of inner phalangeal cells. Our results show that Notch signaling is finely calibrated in the cochlea to produce precisely tuned levels of signaling that first set the boundary of the organ of Corti and later regulate hair cell development.

Funder

National Institute on Deafness and Other Communication Disorders

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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