Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling

  1. Sung-Ho Huh
  2. Mark E Warchol
  3. David M Ornitz  Is a corresponding author
  1. Washington University School of Medicine, United States

Abstract

The sensory and supporting cells of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and supporting cells, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea.

Article and author information

Author details

  1. Sung-Ho Huh

    Departments of Developmental Biology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mark E Warchol

    Departments of Otolaryngology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. David M Ornitz

    Departments of Developmental Biology, Washington University School of Medicine, St Louis, United States
    For correspondence
    dornitz@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Ethics

Animal experimentation: This study was carried out in strict accordance with the recommendations in the Guide for the Careand Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by theWashington University Division of Comparative Medicine Animal Studies Committee (Protocol Number20130201). All efforts were made to minimize animal suffering.

Version history

  1. Received: December 5, 2014
  2. Accepted: April 25, 2015
  3. Accepted Manuscript published: April 27, 2015 (version 1)
  4. Version of Record published: May 18, 2015 (version 2)

Copyright

© 2015, Huh et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,223
    Page views
  • 422
    Downloads
  • 55
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Sung-Ho Huh
  2. Mark E Warchol
  3. David M Ornitz
(2015)
Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling
eLife 4:e05921.
https://doi.org/10.7554/eLife.05921

Share this article

https://doi.org/10.7554/eLife.05921

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tariq Zaman, Daniel Vogt ... Michael R Williams
    Research Article

    The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.