<scp><i>Six1</i></scp> is required for signaling center formation and labial‐lingual asymmetry in developing lower incisors

Takahashi, Masanori; Ikeda, Keiko; Ohmuraya, Masaki; Nakagawa, Yoshiko; Sakuma, Tetsushi; Yamamoto, Takashi; Kawakami, Kiyoshi

doi:10.1002/dvdy.174

Cited by 4 publications

(1 citation statement)

References 62 publications

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“…This finding suggests that SIX1 is required either directly or indirectly for the expression of genes that regulate this pathway. Our in vitro and in vivo data at E10.5, and previous work at later stages during odontogenesis in the mouse, 53 show that despite the fact that SIX1 regulates both, inducers and repressors of WNT, the final outcome is the repression of WNT signaling in the oral region of the mandibular arch where SIX1 is expressed. Based on our work, it seems that SIX1 is accomplishing this repression by several mechanisms that may or may not require induction of Frzb expression in NCCs.…”

Section: Discussionsupporting

confidence: 60%

Transcriptomic analysis reveals the role of SIX1 in mouse cranial neural crest patterning and bone development

Baxi

Jourdeuil

Cox

et al. 2023

Developmental Dynamics

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BackgroundGenetic variants of the transcription factor SIX1 and its co‐factor EYA1 underlie 50% of Branchio‐oto‐renal syndrome (BOR) cases. BOR is characterized by craniofacial defects, including malformed middle ear ossicles leading to conductive hearing loss. In this work, we expand our knowledge of the Six1 gene regulatory network by using a Six1‐null mouse line to assess gene expression profiles of E10.5 mandibular arches, which give rise to the neural crest (NC)‐derived middle ear ossicles and lower jaw, via bulk RNA sequencing.ResultsOur transcriptomic analysis led to the identification of 808 differentially expressed genes that are related to translation, NC cell differentiation, osteogenesis, and chondrogenesis including components of the WNT signaling pathway. As WNT signaling is a known contributor to bone development, we demonstrated that SIX1 is required for expression of the WNT antagonist Frzb in the mandibular arch, and determined that SIX1 expression results in repression of WNT signaling.ConclusionOur results clarify the mechanisms by which SIX1 regulates the development of NC‐derived craniofacial elements that are altered in SIX1‐associated disorders. In addition, this work identifies novel genes that could be causative to this birth defect and establishes a link between SIX1 and WNT signaling during patterning of NC cells.

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Section: Discussionsupporting

confidence: 60%

Transcriptomic analysis reveals the role of SIX1 in mouse cranial neural crest patterning and bone development

Baxi

Jourdeuil

Cox

et al. 2023

Developmental Dynamics

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

Jourdeuil,

Gafurova,

Ben-Mayor

et al. 2024

Preprint

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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.

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Lineage tracing using Wnt2b‐2A‐CreERT2 knock‐in mice reveals the contributions of Wnt2b‐expressing cells to novel subpopulations of mesothelial/epicardial cell lineages during mouse development

Takahashi,

Isagawa,

Sato

et al. 2024

Genes to Cells

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Mesothelial and epicardial cells give rise to various types of mesenchymal cells via epithelial (mesothelial)‐to‐mesenchymal transition during development. However, the genes controlling the differentiation and diversification of mesothelial/epicardial cells remain unclear. Here, we examined Wnt2b expression in the embryonic mesothelium and epicardium and performed lineage tracing of Wnt2b‐expressing cells by using novel Wnt2b‐2A‐CreERT2 knock‐in and LacZ‐reporter mice. Wnt2b was expressed in mesothelial cells covering visceral organs, but the expression was restricted in their subpopulations. Wnt2b‐expressing cells labeled at embryonic day (E) 10.5 were distributed to the mesothelium and mesenchyme in the lungs, abdominal wall, stomach, and spleen in Wnt2b2A‐CreERT2/+;R26RLacZ/+ mice at E13.0. Wnt2b was initially expressed in the proepicardial organ (PEO) at E9.5 and then in the epicardium after E10.0. Wnt2b‐expressing PEO cells labeled at E9.5 differentiated into a small fraction of cardiac fibroblasts and preferentially localized at the left side of the postnatal heart. LacZ+ epicardium‐derived cells labeled at E10.5 differentiated into a small fraction of fibroblasts and smooth muscle cells in the postnatal heart. Taken together, our results reveal novel subpopulations of PEO and mesothelial/epicardial cells that are distinguishable by Wnt2b expression and elucidate the unique contribution of Wnt2b‐expressing PEO and epicardial cells to the postnatal heart.

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Six1 is required for signaling center formation and labial‐lingual asymmetry in developing lower incisors

Cited by 4 publications

References 62 publications

Transcriptomic analysis reveals the role of SIX1 in mouse cranial neural crest patterning and bone development

Transcriptomic analysis reveals the role of SIX1 in mouse cranial neural crest patterning and bone development

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

Lineage tracing using Wnt2b‐2A‐CreERT2 knock‐in mice reveals the contributions of Wnt2b‐expressing cells to novel subpopulations of mesothelial/epicardial cell lineages during mouse development

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