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Updated: Jul 21, 2025

Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis
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Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis

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

Anthony J Asmar1, Shaun R Abrams1,2, Jenny Hsin2

  • 1Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.

Nature Communications
|July 26, 2023
PubMed

Insights

A newly discovered pathway uses the ubiquitin ligase CRL3-KLHL4 to inhibit CDC42 signaling, crucial for embryonic development of the face, brain, and skin.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The precise molecular mechanisms governing embryonic ectoderm patterning into neural, epidermal, and craniofacial lineages remain elusive.
  • Understanding these processes is vital for comprehending congenital disorders affecting facial and neural development.

Purpose of the Study:

  • To elucidate the posttranslational pathway regulating early ectodermal differentiation in the vertebrate head.
  • To identify key molecular players coordinating cell-fate decisions during embryonic development.

Main Methods:

  • Biochemical disease-variant profiling to identify regulatory pathways.
  • Analysis of the CRL3-KLHL4 ubiquitin ligase and its interaction with CDC42 signaling components.
  • Investigation of PAK1 ubiquitylation and its functional consequences.

Main Results:

  • CRL3-KLHL4 restricts CDC42 signaling by monoubiquitylating PAK1, converting it into a CDC42 inhibitor.
  • Loss of CRL3-KLHL4 or disease-associated KLHL4 variants impair PAK1 ubiquitylation, leading to CDC42 overactivation.
  • Defective ectodermal patterning and neurulation observed in the absence of proper CRL3-KLHL4 function.

Conclusions:

  • A ubiquitin-dependent mechanism restricting CDC42 signaling is essential for vertebrate head development.
  • This pathway coordinates cell-fate determination and morphogenetic changes for proper organogenesis.
  • Dysregulation of this pathway contributes to developmental defects in craniofacial and neural structures.

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