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Thyroid bud morphogenesis requires CDC42- and SHROOM3-dependent apical constriction
David A F Loebel1, Timothy F Plageman2, Theresa L Tang3
1Embryology Unit, Children's Medical Research Institute, Locked Bag 32, Wentworthville, New South Wales 2145, Australia Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia dloebel@cmri.org.au.
Abstract:
Early development of the gut endoderm and its subsequent remodeling for the formation of organ buds are accompanied by changes to epithelial cell shape and polarity. Members of the Rho-related family of small GTPases and their interacting proteins play multiple roles in regulating epithelial morphogenesis. In this study we examined the role of Cdc42 in foregut development and organ bud formation. Ablation of Cdc42 in post-gastrulation mouse embryos resulted in a loss of apical-basal cell polarity and columnar epithelial morphology in the ventral pharyngeal endoderm, in conjunction with a loss of apical localization of the known CDC42 effector protein PARD6B. Cell viability but not proliferation in the foregut endoderm was impaired. Outgrowth of the liver, lung and thyroid buds was severely curtailed in Cdc42-deficient embryos. In particular, the thyroid bud epithelium did not display the apical constriction that normally occurs concurrently with the outgrowth of the bud into the underlying mesenchyme. SHROOM3, a protein that interacts with Rho GTPases and promotes apical constriction, was strongly expressed in the thyroid bud and its sub-cellular localization was disrupted in Cdc42-deficient embryos. In Shroom3 gene trap mutant embryos, the thyroid bud epithelium showed no apical constriction, while the bud continued to grow and protruded into the foregut lumen. Our findings indicate that Cdc42 is required for epithelial polarity and organization in the endoderm and for apical constriction in the thyroid bud. It is possible that the function of CDC42 is partly mediated by SHROOM3.
Insights
Cdc42 (Cell division control protein 42) is essential for early embryonic development, maintaining epithelial cell polarity and organization in the foregut. Its absence impairs organ bud formation, particularly thyroid development, by disrupting apical constriction.
Area of Science:
- Developmental Biology
- Cell Biology
- Genetics
Background:
- Epithelial morphogenesis during early organogenesis involves dynamic changes in cell shape and polarity.
- Rho GTPases, including Cdc42, are critical regulators of these cellular processes.
- The specific roles of Cdc42 in foregut development and organ bud formation remain incompletely understood.
Purpose of the Study:
- To investigate the function of Cdc42 in mouse foregut development and the formation of embryonic organ buds.
- To determine the impact of Cdc42 ablation on epithelial cell polarity, morphology, and organogenesis.
- To explore the potential involvement of SHROOM3 in Cdc42-mediated apical constriction.
Main Methods:
- Conditional ablation of Cdc42 in mouse embryos post-gastrulation.
- Analysis of epithelial cell polarity, morphology, and viability in the ventral pharyngeal endoderm.
- Assessment of liver, lung, and thyroid bud outgrowth and morphology.
- Examination of SHROOM3 expression and localization in wild-type and Cdc42-deficient embryos.
- Analysis of Shroom3 gene trap mutant embryos.
Main Results:
- Cdc42 deficiency led to loss of apical-basal polarity and columnar epithelial morphology in the ventral pharyngeal endoderm.
- Cell viability was impaired, but proliferation was unaffected in the foregut endoderm of Cdc42-deficient embryos.
- Outgrowth of liver, lung, and thyroid buds was severely reduced; thyroid bud apical constriction was absent.
- SHROOM3 localization was disrupted in Cdc42-deficient embryos, and Shroom3 mutants also lacked thyroid bud apical constriction.
Conclusions:
- Cdc42 is indispensable for maintaining epithelial polarity and organization in the developing foregut endoderm.
- Cdc42 plays a crucial role in apical constriction during thyroid bud formation, potentially via SHROOM3.
- These findings highlight Cdc42's importance in regulating epithelial morphogenesis for successful organogenesis.
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