Mcrs1 interacts with Six1 to influence early craniofacial and otic development

Neilson, Karen M.; Keer, Stephanie; Bousquet, Nicole; Macrorie, Olivia; Majumdar, Himani Datta; Kenyon, Kristy L.; Alfandari, Dominique; Moody, Sally A.

doi:10.1016/j.ydbio.2020.08.013

Cited by 15 publications

(18 citation statements)

References 45 publications

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“…Previous work from our lab and others showed that Six1 functions at early stages of placode formation (Christophorou et al, 2009;Brugmann et al, 2004), during otic vesicle patterning (Zheng et al, 2003;Ozaki et al, 2004;Laclef et al, 2003) and hair cell formation in the inner ear (Zhang et al, 2017;Li et al, 2020;Ahmed et al, 2012). One important characteristic of Six1 factors that allows them to act in different contexts is their interaction with co-factors that modulate their transcriptional activities (Neilson et al, 2020(Neilson et al, , 2017Li et al, 2003Li et al, , 2020Kenyon et al, 2005a,b;Heanue et al, 1999;Guo et al, 2011;Brugmann et al, 2004;Ahmed et al, 2012).…”

Section: Discussionmentioning

confidence: 92%

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development

et al. 2021

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Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, craniofacial and/or renal defects. Variants 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 variants 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 interferes with the transcriptional activation of Six1+Eya1 target genes. 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 variant 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.

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Section: Discussionmentioning

confidence: 92%

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development

et al. 2021

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“…It has been proposed that phenotypic variability in BOR is caused by a dosage effect in which the amount of available protein determines development of an embryonic structure as a certain threshold needs to be exceeded for expression of different genes 42,43 . In addition, as SIX1 function relies on co‐factor interaction, 33,44‐46 association with different co‐factors could vary based on the amount of SIX1 protein available, which in turn would lead to different patterns of gene expression. Two reported SIX1 variants (Q11X and Q22X) generate a truncated protein that is degraded (data not shown) what would match the Six1‐het genotype.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 It has been proposed that phenotypic variability in BOR is caused by a dosage effect in which the amount of available protein determines development of an embryonic structure as a certain threshold needs to be exceeded for expression of different genes. 42,43 In addition, as SIX1 function relies on co-factor interaction, 33,[44][45][46] craniofacial development differently. 26 Environmental factors and genetic modifiers are another possible explanation to the phenotypic and transcriptomic variabilities.…”

Section: Transcriptomic Analysis Identified a Link Between Six1 And T...mentioning

confidence: 99%

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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“…Other regulators of Six1 transcriptional activity are binding partners. Six1 represses transcription via binding to Groucho/TLE proteins, and activates transcription via binding to Eya proteins, and the latter effect can be attenuated by other proteins in the complex such as Pa2G4 and Mcrs1 [ 43 , 69 ]. Therefore, the mode of Six1 activity reported herein is likely also dependent upon which cofactors, of which there are several candidates [ 56 ], are available.…”

Section: Discussionmentioning

confidence: 99%

“…Together, these studies indicate that the R110W variant acts as a hypomorph by rendering Six1 less effective at repressing target genes. Since R110W can bind cytosolic Eya1 and transport it to the nucleus and bind DNA, we posit that this loss of activity may be due to interference with the binding of cofactors that mediate transcriptional repression, such as Groucho/TLE, Pa2G4 and Mcrs1 [ 43 , 56 , 69 ]. It is interesting that at high levels of expression, it can have either the same activity as exogenous Six1WT or the opposite activity, depending on the target gene.…”

Section: Discussionmentioning

confidence: 99%

Mutations in SIX1 Associated with Branchio-oto-Renal Syndrome (BOR) Differentially Affect Otic Expression of Putative Target Genes

Mehdizadeh

Majumdar

Ahsan

et al. 2021

JDB

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Several single-nucleotide mutations in SIX1 underlie branchio-otic/branchio-oto-renal (BOR) syndrome, but the clinical literature has not been able to correlate different variants with specific phenotypes. We previously assessed whether variants in either the cofactor binding domain (V17E, R110W) or the DNA binding domain (W122R, Y129C) might differentially affect early embryonic gene expression, and found that each variant had a different combination of effects on neural crest and placode gene expression. Since the otic vesicle gives rise to the inner ear, which is consistently affected in BOR, herein we focused on whether the variants differentially affected the otic expression of genes previously found to be likely Six1 targets. We found that V17E, which does not bind Eya cofactors, was as effective as wild-type Six1 in reducing most otic target genes, whereas R110W, W122R and Y129C, which bind Eya, were significantly less effective. Notably, V17E reduced the otic expression of prdm1, whereas R110W, W122R and Y129C expanded it. Since each mutant has defective transcriptional activity but differs in their ability to interact with Eya cofactors, we propose that altered cofactor interactions at the mutated sites differentially interfere with their ability to drive otic gene expression, and these differences may contribute to patient phenotype variability.

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Mcrs1 interacts with Six1 to influence early craniofacial and otic development

Cited by 15 publications

References 45 publications

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development

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

Mutations in SIX1 Associated with Branchio-oto-Renal Syndrome (BOR) Differentially Affect Otic Expression of Putative Target Genes

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