Delineating the roles of Grhl2 in craniofacial development through tissue-specific conditional deletion and epistasis approaches in mouse

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dc.contributor.authorde Vries, M.
dc.contributor.authorOwens, H.G.
dc.contributor.authorCarpinelli, M.R.
dc.contributor.authorPartridge, D.
dc.contributor.authorKersbergen, A.
dc.contributor.authorSutherland, K.D.
dc.contributor.authorAuden, A.
dc.contributor.authorAnderson, P.J.
dc.contributor.authorJane, S.M.
dc.contributor.authorDworkin, S.
dc.date.issued2021
dc.description.abstractBackground The highly conserved Grainyhead-like (Grhl) family of transcription factors play critical roles in the development of the neural tube and craniofacial skeleton. In particular, deletion of family member Grainyhead-like 2 (Grhl2) leads to mid-gestational embryonic lethality, maxillary clefting, abdominoschisis, and both cranial and caudal neural tube closure defects. These highly pleiotropic and systemic defects suggest that Grhl2 plays numerous critical developmental roles to ensure correct morphogenesis and patterning. Results Here, using four separate Cre-lox conditional deletion models, as well as one genetic epistasis approach (Grhl2+/−;Edn1+/− double heterozygous mice) we have investigated tissue-specific roles of Grhl2 in embryonic development, with a particular focus on the craniofacial skeleton. We find that loss of Grhl2 in the pharyngeal epithelium (using the ShhCre driver) leads to low-penetrance micrognathia, whereas deletion of Grhl2 within the ectoderm of the pharynx (NestinCre) leads to small, albeit significant, differences in the proximal-distal elongation of both the maxilla and mandible. Loss of Grhl2 in endoderm (Sox17-2aiCre) resulted in noticeable lung defects and a single instance of secondary palatal clefting, although formation of other endoderm-derived organs such as the stomach, bladder and intestines was not affected. Lastly, deletion of Grhl2 in cells of the neural crest (Wnt1Cre) did not lead to any discernible defects in craniofacial development, and similarly, our epistasis approach did not detect any phenotypic consequences of loss of a single allele of both Grhl2 and Edn1. Conclusion Taken together, our study identifies a pharyngeal-epithelium intrinsic, non-cell-autonomous role for Grhl2 in the patterning and formation of the craniofacial skeleton, as well as an endoderm-specific role for Grhl2 in the formation and establishment of the mammalian lung.
dc.description.statementofresponsibilityMichael de Vries, Harley G. Owens, Marina R. Carpinelli, Darren Partridge, Ariena Kersbergen, Kate D. Sutherland ... et al.
dc.identifier.citationDevelopmental Dynamics, 2021; 250(8):1191-1209
dc.identifier.doi10.1002/dvdy.322
dc.identifier.issn1058-8388
dc.identifier.issn1097-0177
dc.identifier.orcidAnderson, P.J. [0000-0002-3730-4652]
dc.identifier.urihttps://hdl.handle.net/2440/132460
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/arc/DE140100500
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1063837
dc.rights© 2021 American Association for Anatomy
dc.source.urihttps://doi.org/10.1002/dvdy.322
dc.subjectGrainyhead-like
dc.subjectcraniofacial development
dc.subjectendoderm
dc.subjectlung development
dc.subjectmicrognathia
dc.subjecttranscription factor
dc.titleDelineating the roles of Grhl2 in craniofacial development through tissue-specific conditional deletion and epistasis approaches in mouse
dc.typeJournal article
pubs.publication-statusPublished

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