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Updated: Jul 21, 2025
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Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis
Published on: April 1, 2022
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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
Summary
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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