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    Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

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    Author
    Carpinelli, MR; de Vries, ME; Auden, A; Butt, T; Deng, Z; Partridge, DD; Miles, LB; Georgy, SR; Haigh, JJ; Darido, C; ...
    Date
    2020-03-01
    Source Title
    Disease Models and Mechanisms
    Publisher
    COMPANY BIOLOGISTS LTD
    University of Melbourne Author/s
    Darido, Charbel
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Carpinelli, M. R., de Vries, M. E., Auden, A., Butt, T., Deng, Z., Partridge, D. D., Miles, L. B., Georgy, S. R., Haigh, J. J., Darido, C., Brabletz, S., Brabletz, T., Stemmler, M. P., Dworkin, S. & Jane, S. M. (2020). Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure. DISEASE MODELS & MECHANISMS, 13 (3), https://doi.org/10.1242/dmm.042218.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251982
    DOI
    10.1242/dmm.042218
    Abstract
    Cleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2-null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelial-mesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1-/- mice is evident, with rescue of both palatal and facial fusion seen in Grhl2-/-;Zeb1-/- embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

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