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A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development

Author

Listed:
  • Anthony J. Asmar

    (National Institutes of Health)

  • Shaun R. Abrams

    (National Institutes of Health
    National Institutes of Health)

  • Jenny Hsin

    (National Institutes of Health)

  • Jason C. Collins

    (National Institutes of Health)

  • Rita M. Yazejian

    (National Institutes of Health)

  • Youmei Wu

    (National Institutes of Health)

  • Jean Cho

    (National Institutes of Health)

  • Andrew D. Doyle

    (National Institutes of Health)

  • Samhitha Cinthala

    (National Institutes of Health)

  • Marleen Simon

    (University Medical Center Utrecht)

  • Richard H. Jaarsveld

    (University Medical Center Utrecht)

  • David B. Beck

    (New York University Grossman School of Medicine
    New York University Grossman School of Medicine)

  • Laura Kerosuo

    (National Institutes of Health)

  • Achim Werner

    (National Institutes of Health)

Abstract

The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural crest-derived craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. This regulation relies on the CDC42-activating complex GIT1-βPIX, which CRL3-KLHL4 exploits as a substrate-specific co-adaptor to recognize and monoubiquitylate PAK1. Surprisingly, we find that ubiquitylation converts the canonical CDC42 effector PAK1 into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific restriction of CDC42 signaling by a ubiquitin-based effector-to-inhibitor is essential for early face, brain, and skin formation, revealing how cell-fate and morphometric changes are coordinated to ensure faithful organ development.

Suggested Citation

  • Anthony J. Asmar & Shaun R. Abrams & Jenny Hsin & Jason C. Collins & Rita M. Yazejian & Youmei Wu & Jean Cho & Andrew D. Doyle & Samhitha Cinthala & Marleen Simon & Richard H. Jaarsveld & David B. Bec, 2023. "A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40223-y
    DOI: 10.1038/s41467-023-40223-y
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