Differential regulation of cranial and cardiac neural crest by serum response factor and its cofactors

  1. Colin J Dinsmore
  2. Philippe Soriano  Is a corresponding author
  1. Icahn School of Medicine at Mount Sinai, United States

Abstract

Serum response factor (SRF) is an essential transcription factor that influences many cellular processes including cell proliferation, migration, and differentiation. SRF directly regulates and is required for immediate early gene (IEG) and actin cytoskeleton-related gene expression. SRF coordinates these competing transcription programs through discrete sets of cofactors, the Ternary Complex Factors (TCFs) and Myocardin Related Transcription Factors (MRTFs). The relative contribution of these two programs to in vivo SRF activity and mutant phenotypes is not fully understood. To study how SRF utilizes its cofactors during development, we generated a knock-in SrfaI allele in mice harboring point mutations that disrupt SRF-MRTF-DNA complex formation but leave SRF-TCF activity unaffected. Homozygous SrfaI/aI mutants die at E10.5 with notable cardiovascular phenotypes, and neural crest conditional mutants succumb at birth to defects of the cardiac outflow tract but display none of the craniofacial phenotypes associated with complete loss of SRF in that lineage. Our studies further support an important role for MRTF mediating SRF function in cardiac neural crest and suggest new mechanisms by which SRF regulates transcription during development.

Data availability

The NGS data is available on GEO. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE186770

The following data sets were generated

Article and author information

Author details

  1. Colin J Dinsmore

    Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Philippe Soriano

    Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    philippe.soriano@mssm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0427-926X

Funding

National Institute of Dental and Craniofacial Research (R01 DE022363)

  • Philippe Soriano

National Institute of Dental and Craniofacial Research (F32 DE026678)

  • Colin J Dinsmore

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 experimentation was conducted according to protocols approved by the Institutional Animal Care and Use Committee of the Icahn School of Medicine at Mount Sinai under protocol LA11-00243. Mice were kept in a dedicated animal vivarium with veterinarian support. They were housed on a 13hr-11hr light-dark cycle and had access to food and water ad libitum.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Preprint posted: October 28, 2021 (view preprint)
  2. Received: October 28, 2021
  3. Accepted: January 18, 2022
  4. Accepted Manuscript published: January 19, 2022 (version 1)
  5. Version of Record published: February 1, 2022 (version 2)

Copyright

© 2022, Dinsmore & Soriano

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

  • 1,126
    Page views
  • 132
    Downloads
  • 2
    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. Colin J Dinsmore
  2. Philippe Soriano
(2022)
Differential regulation of cranial and cardiac neural crest by serum response factor and its cofactors
eLife 11:e75106.
https://doi.org/10.7554/eLife.75106

Further reading

    1. Developmental Biology
    Ke Xu, Xianwei Su ... Hongbin Liu
    Research Article

    The acrosome is a membranous organelle positioned in the anterior portion of the sperm head and is essential for male fertility. Acrosome biogenesis requires the dynamic cytoskeletal shuttling of vesicles towards nascent acrosome which is regulated by a series of accessory proteins. However, much remains unknown about the molecular basis underlying this process. Here, we generated Ssh2 knock-out (KO) mice and HA-tagged Ssh2 knock-in (KI) mice to define the functions of Slingshot phosphatase 2 (SSH2) in spermatogenesis and demonstrated that as a regulator of actin remodeling, SSH2 is essential for acrosome biogenesis and male fertility. In Ssh2 KO males, spermatogenesis was arrested at the early spermatid stage with increased apoptotic index and the impaired acrosome biogenesis was characterized by defective transport/fusion of proacrosomal vesicles. Moreover, disorganized F-actin structures accompanied by excessive phosphorylation of COFILIN were observed in the testes of Ssh2 KO mice. Collectively, our data reveal a modulatory role for SSH2 in acrosome biogenesis through COFILIN-mediated actin remodeling and the indispensability of this phosphatase in male fertility in mice.

    1. Developmental Biology
    2. Evolutionary Biology
    Erliang Yuan, Huijuan Guo ... Yucheng Sun
    Research Article

    Wing dimorphism in insects is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between dispersing and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that, while developing normally in winged-destined pea aphids, the wing disc in wingless-destined aphids degenerated 30-hr postbirth and that this degeneration was due to autophagy rather than apoptosis. Activation of autophagy in first instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. REPTOR2, associated with TOR signaling pathway, was identified by RNA-seq as a differentially expressed gene between the two morphs with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event that occurred exclusively in pea aphids on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTOR’s canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. Co-suppression of TOR and REPTOR2 showed that dsREPTOR2 could mask the positive effect of dsTOR on autophagy, suggesting that REPTOR2 acted as a key regulator downstream of TOR in the signaling pathway. These results revealed that the TOR signaling pathway suppressed autophagic degradation of the wing disc in pea aphids by negatively regulating the expression of REPTOR2.