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Control of craniofacial and brain development by Cullin3-RING ubiquitin ligases: Lessons from human disease genetics
Anthony J Asmar1, David B Beck2, Achim Werner1
1Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
Abstract:
Metazoan development relies on intricate cell differentiation, communication, and migration pathways, which ensure proper formation of specialized cell types, tissues, and organs. These pathways are crucially controlled by ubiquitylation, a reversible post-translational modification that regulates the stability, activity, localization, or interaction landscape of substrate proteins. Specificity of ubiquitylation is ensured by E3 ligases, which bind substrates and co-operate with E1 and E2 enzymes to mediate ubiquitin transfer. Cullin3-RING ligases (CRL3s) are a large class of multi-subunit E3s that have emerged as important regulators of cell differentiation and development. In particular, recent evidence from human disease genetics, animal models, and mechanistic studies have established their involvement in the control of craniofacial and brain development. Here, we summarize regulatory principles of CRL3 assembly, substrate recruitment, and ubiquitylation that allow this class of E3s to fulfill their manifold functions in development. We further review our current mechanistic understanding of how specific CRL3 complexes orchestrate neuroectodermal differentiation and highlight diseases associated with their dysregulation. Based on evidence from human disease genetics, we propose that other unknown CRL3 complexes must help coordinate craniofacial and brain development and discuss how combining emerging strategies from the field of disease gene discovery with biochemical and human pluripotent stem cell approaches will likely facilitate their identification.
Insights
Cullin3-RING ligases (CRL3s) are vital E3 enzymes regulating cell differentiation and development. Dysregulation of CRL3s contributes to craniofacial and brain disorders, with more unknown CRL3s likely involved.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Metazoan development involves complex cell processes controlled by ubiquitylation, a key post-translational modification.
- E3 ligases, particularly Cullin3-RING ligases (CRL3s), are crucial for regulating protein stability and function during development.
- CRL3s play significant roles in cell differentiation and have been implicated in craniofacial and brain development.
Purpose of the Study:
- To summarize the regulatory mechanisms of CRL3 complex assembly, substrate recruitment, and ubiquitylation.
- To review the mechanistic understanding of CRL3 complexes in neuroectodermal differentiation.
- To highlight diseases linked to CRL3 dysregulation and propose future research directions.
Main Methods:
- Literature review of regulatory principles of CRL3s.
- Analysis of mechanistic studies on CRL3 function in development.
- Examination of human disease genetics and animal models related to CRL3s.
Main Results:
- CRL3s are essential regulators of cell differentiation, communication, and migration.
- Specific CRL3 complexes orchestrate neuroectodermal differentiation, and their dysregulation leads to developmental diseases.
- Evidence suggests the existence of additional, yet unidentified, CRL3 complexes involved in craniofacial and brain development.
Conclusions:
- CRL3s are critical for normal development, particularly neuroectodermal differentiation.
- Dysregulation of CRL3s is associated with human diseases affecting craniofacial and brain development.
- Future research combining disease gene discovery, biochemistry, and stem cell models will identify novel CRL3 complexes and their roles.
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