Evolutionary changes in transcription factor coding sequence quantitatively alter sensory organ development and function

  1. Simon Weinberger
  2. Matthew P Topping
  3. Jiekun Yan
  4. Annelies Claeys
  5. Natalie De Geest
  6. Duru Ozbay
  7. Talah Hassan
  8. Xiaoli He
  9. Joerg T Albert
  10. Bassem A Hassan  Is a corresponding author
  11. Ariane Ramaekers  Is a corresponding author
  1. VIB Center for the Biology of Disease, Belgium
  2. University College London, United Kingdom
  3. ICM, France

Abstract

'Toolkit' genes are highly conserved developmental regulators. While changes in their regulatory elements contribute to morphological evolution, the role of coding sequence (CDS) evolution remains unresolved. We used CDS-specific knock-ins of the proneural transcription factor Atonal homologs (ATHs) to address this question. Drosophila Atonal CDS was endogenously replaced with that of distant ATHs at key phylogenetic positions, non-ATH proneural genes, and the closest CDS to ancestral proneural genes. ATHs and the ancestral-like gene rescued sensory organ fate in atonal mutants, in contrast to non-ATHs. Surprisingly, different ATHs displayed a gradient of quantitative variation in proneural activity and the number and functionality of sense organs. This proneural potency gradient correlated directly with ATH protein stability, including in response to Notch signaling, independently of mRNA levels or codon usage. This establishes a distinct and ancient function for ATHs and demonstrates that CDS evolution can underlie quantitative variation in sensory development and function.

Article and author information

Author details

  1. Simon Weinberger

    VIB Center for the Biology of Disease, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthew P Topping

    Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jiekun Yan

    VIB Center for the Biology of Disease, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Annelies Claeys

    VIB Center for the Biology of Disease, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Natalie De Geest

    VIB Center for the Biology of Disease, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Duru Ozbay

    VIB Center for the Biology of Disease, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Talah Hassan

    Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiaoli He

    Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Joerg T Albert

    Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Bassem A Hassan

    Brain Development, ICM, Paris, France
    For correspondence
    bassem.hassan@icm-institute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9533-4908
  11. Ariane Ramaekers

    VIB Center for the Biology of Disease, Leuven, Belgium
    For correspondence
    ariane.ramaekers@icm-institute.org
    Competing interests
    The authors declare that no competing interests exist.

Funding

Vlaams Instituut voor Biotechnologie

  • Simon Weinberger
  • Jiekun Yan
  • Annelies Claeys
  • Natalie De Geest
  • Duru Ozbay
  • Bassem A Hassan
  • Ariane Ramaekers

Fonds Wetenschappelijk Onderzoek

  • Simon Weinberger
  • Jiekun Yan
  • Annelies Claeys
  • Natalie De Geest
  • Duru Ozbay
  • Bassem A Hassan
  • Ariane Ramaekers

BELSPO

  • Simon Weinberger
  • Jiekun Yan
  • Annelies Claeys
  • Natalie De Geest
  • Duru Ozbay
  • Bassem A Hassan
  • Ariane Ramaekers

European Commission

  • Simon Weinberger
  • Bassem A Hassan

Human Frontier Science Program

  • Matthew P Topping
  • Talah Hassan
  • Xiaoli He
  • Joerg T Albert

Biotechnology and Biological Sciences Research Council

  • Matthew P Topping
  • Talah Hassan
  • Xiaoli He
  • Joerg T Albert

Paul G. Allen Family Foundation

  • Bassem A Hassan

Einstein Stiftung Berlin

  • Bassem A Hassan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Version history

  1. Received: February 27, 2017
  2. Accepted: March 27, 2017
  3. Accepted Manuscript published: April 13, 2017 (version 1)
  4. Version of Record published: May 15, 2017 (version 2)

Copyright

© 2017, Weinberger 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

  • 4,736
    Page views
  • 400
    Downloads
  • 21
    Citations

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

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. Simon Weinberger
  2. Matthew P Topping
  3. Jiekun Yan
  4. Annelies Claeys
  5. Natalie De Geest
  6. Duru Ozbay
  7. Talah Hassan
  8. Xiaoli He
  9. Joerg T Albert
  10. Bassem A Hassan
  11. Ariane Ramaekers
(2017)
Evolutionary changes in transcription factor coding sequence quantitatively alter sensory organ development and function
eLife 6:e26402.
https://doi.org/10.7554/eLife.26402

Share this article

https://doi.org/10.7554/eLife.26402

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.