Biology subjects

Jourdeuil, K.

Publications and source records attributed to Jourdeuil, K..

3 recordsLinked to original sources

bioRxiv2024

Direct and Indirect Regulation of SIX1+EYA Transcriptional Activity by PA2G4, MCRS1, and SOBP

Branchio-oto-renal (BOR) syndrome is an autosomal dominant condition characterized by variable craniofacial malformations, hearing loss and in some patients, renal dysfunction. Recently, a clinical study showed that patients with mutations causative of BOR also present with craniosynostosis, indicating that this could be an undiagnosed feature of BOR. Approximately half of all patients presenting with BOR have a variant in either SIX1 or its activating co-factor EYA1. The genes underlying BOR in the other 50% of patients remain unknown. To date, most studies on the role of SIX1 in the inner ear have focused on its role in the placode-based development of the sensorineural epithelia (cochlear and vestibular organs), as sensorineural hearing loss has long term effects on human health and development. The role of SIX1 in the neural crest cells (NCCs) of the first pharyngeal (a.k.a., mandibular) arch, which will give rise to the upper and lower jaws as well as the middle ear ossicles which may be affected in patients with BOR, is less well understood. To that end, we examine herein the role of three proteins that have been identified in Xenopus laevis as SIX1 co-factors to determine whether their function as regulators of SIX1+EYA transcriptional activity is conserved in mouse and begin to elucidate their function in the NCCs of the mandibular arch. Our data reveal that SIX1 is co-expressed with PA2G4, MCRS1, and SOBP within the oral domain of the mandibular arch, although each has a very distinct expression pattern. We further demonstrate that MCRS1 and SOBP are bona fide SIX1 co-factors that can repress SIX1+EYA transcriptional activity. PA2G4, on the other hand, does not bind to SIX1 in the mouse but can indirectly enhance the transcriptional activity of the SIX1+EYA transcriptional complex. Further, we show that both MCRS1 and SOBP are also able to translocate EYA to the nucleus via direct (i.e., SOBP) or indirect (i.e., MCRS1) mechanisms. We also show that later, during development of the mandible and incisors that SOBP is co-expressed with SIX1 within these anlagen, confirming the biological relevance of these transcriptional complexes in craniofacial bone formation and within the derivatives of the mandibular NCCs. This study, therefore, highlights the complexity of SIX1+EYA transcriptional regulation suggesting that there are multiple, and potentially redundant, mechanisms in place to ensure precise levels of SIX1+EYA transcriptional activity during craniofacial development.

developmental biology↗

bioRxiv2021

Sobp modulates Six1 transcriptional activation and is required during craniofacial development

Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, craniofacial and/or renal defects. Mutations in the transcription factor Six1 and its cofactor Eya1, both required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 cofactor and SOBP mutations in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-IP and immunofluorescence experiments demonstrate that Sobp binds to and co-localizes with Six1 in the cell nucleus. Luciferase assays show that Sobp represses Six1+Eya1 transcriptional activation. Experiments in Xenopus embryos that either knockdown or increase expression show that Sobp is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human mutation disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function, is required for vertebrate craniofacial development, and identifies Sobp as a potential candidate gene for BOR and other deafness syndromes. Summary statementSobp interacts with Six1 in the cell nucleus and represses the Six1+Eya1 transcriptional activation. In Xenopus embryos, Sobp functions during early stages of inner ear development.

developmental biology↗

bioRxiv2019

Connexin 43 impacts the chick premigratory cranial neural crest cell population without affecting the neural crest cell epithelial-to-mesenchymal transition

Gap junctions are intercellular channels that allow for the diffusion of small ions and solutes between coupled cells. Connexin 43 (Cx43), also known as Gap Junction Protein 1, is the most broadly expressed gap junction protein in vertebrate development. Cx43 is strongly expressed in premigratory cranial neural crest cells and is maintained throughout the neural crest cell epithelial-to-mesenchymal transition (EMT), but its function in these cells is not known. To this end, we have used a combination of in vivo and ex vivo live imaging with confocal microscopy, immunohistochemistry, and functional assays to assess gap junction formation, and Cx43 function, in chick premigratory cranial neural crest cells. Our results demonstrate that gap junctions exist between chick premigratory and migratory cranial neural crest cells, with Cx43 depletion inhibiting the function of gap junctions. While a reduction in Cx43 levels just prior to neural crest cell EMT did not affect EMT and subsequent emigration of neural crest cells from the neural tube, the size of the premigratory neural crest cell domain was decreased in the absence of any changes in cell proliferation or death. Collectively, these data identify a role for Cx43 within the chick premigratory cranial neural crest cell population prior to EMT and migration.

developmental biology↗