Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure

  1. Eric R Brooks
  2. Mohammed Tarek Islam
  3. Kathryn V Anderson
  4. Jennifer A Zallen  Is a corresponding author
  1. Sloan Kettering Institute, United States

Abstract

Neural tube closure defects are a major cause of infant mortality, with exencephaly accounting for nearly one-third of cases. However, the mechanisms of cranial neural tube closure are not well understood. Here we show that this process involves a tissue-wide pattern of apical constriction controlled by Sonic hedgehog (Shh) signaling. Midline cells in the mouse midbrain neuroepithelium are short with large apical surfaces, whereas lateral cells are taller and undergo synchronous apical constriction, driving neural fold elevation. Embryos lacking the Shh effector Gli2 fail to produce appropriate midline cell architecture, whereas embryos with expanded Shh signaling, including the IFT-A complex mutants Ift122 and Ttc21b and embryos expressing activated Smoothened, display apical constriction defects in lateral cells. Disruption of lateral, but not midline, cell remodeling results in exencephaly. These results reveal a morphogenetic program of patterned apical constriction governed by Shh signaling that generates structural changes in the developing mammalian brain.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Eric R Brooks

    Developmental Biology Program, Sloan Kettering Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3159-8626
  2. Mohammed Tarek Islam

    Developmental Biology Program, Sloan Kettering Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kathryn V Anderson

    Developmental Biology Program, Sloan Kettering Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jennifer A Zallen

    Developmental Biology Program, Sloan Kettering Institute, New York, United States
    For correspondence
    zallenj@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3975-1568

Funding

Howard Hughes Medical Institute

  • Jennifer A Zallen

National Institutes of Health (F32 NS098832)

  • Eric R Brooks

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

Ethics

Animal experimentation: All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and an approved Institutional Animal Care and Use Committee protocol (15-08-13) of Memorial Sloan Kettering Cancer Center.

Copyright

© 2020, Brooks 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

  • 3,771
    views
  • 494
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Eric R Brooks
  2. Mohammed Tarek Islam
  3. Kathryn V Anderson
  4. Jennifer A Zallen
(2020)
Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure
eLife 9:e60234.
https://doi.org/10.7554/eLife.60234

Share this article

https://doi.org/10.7554/eLife.60234

Further reading

    1. Cancer Biology
    2. Cell Biology
    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.

    1. Cell Biology
    Dan Wu, Venkateswararao Eeda ... Weidong Wang
    Research Article

    Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional ‘M1-like’ CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the ‘M1-like’ CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and ‘M1-like’ ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.