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Ubiquitin ligases: guardians of mammalian development

Abstract

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.

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Fig. 1: E3 ligase classes and ubiquitin transfer mechanisms.
Fig. 2: E3 ligases at key stages of human development.
Fig. 3: E3 ligases throughout human development: trophoblast cell invasion and neural tube closure.
Fig. 4: E3 ligases throughout human development: nervous system development.
Fig. 5: E3 ligases throughout human development: muscle development and innervation.
Fig. 6: Chemical approaches to exploit E3 ligases.

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Acknowledgements

Research conducted by K.M.Y. and D.A.C.W. is supported by the Intramural Research Program of the National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research (ZIA-DE000525 and ZIA-DE000719). Z.C. and A.N.B. receive funding from Cancer Research UK (grant reference DRCNPG\100002) as well as the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan and Diamond Light Source Limited.

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D.A.C.W., K.M.Y., A.N.B. and Z.C. contributed to the conceptualization, writing and revisions of the manuscript. D.A.C.W. and K.M.Y. wrote the first draft and final revisions of the manuscript. Z.C. and A.N.B. reviewed and added to the first draft and revisions of the manuscript. D.A.C.W. and Z.C. prepared the figures.

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Correspondence to David A. Cruz Walma or Kenneth M. Yamada.

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Nature Reviews Molecular Cell Biology thanks Izabela Sumara; Yogesh Kulathu, who co-reviewed with Matthew McFarland; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Pre-eclampsia

A toxic medical condition during late pregnancy characterized by high blood pressure, oedema and protein in the urine.

Intrauterine growth restriction

Abnormally slow growth of the fetus defined as less than 10% of predicted body weight for gestational age.

Focal adhesion

A subcellular structure containing protein complexes mediating the adhesion of cells to the extracellular matrix.

Midline

A topographical line formed during gastrulation defined by the formation of the notochord that extends from the anterior to the posterior of the embryo that helps define the future embryonic axes.

Epithelial–mesenchymal transition

(EMT). The conversion of epithelial cells to migratory fibroblast-like mesenchymal cells by an intracellular regulatory process.

Thalidomide

A small-molecule drug originally intended for use as a sedative and to relieve pregnancy-induced nausea but found to cause birth defects, particularly limb malformations.

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Cruz Walma, D.A., Chen, Z., Bullock, A.N. et al. Ubiquitin ligases: guardians of mammalian development. Nat Rev Mol Cell Biol 23, 350–367 (2022). https://doi.org/10.1038/s41580-021-00448-5

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