Six1 and Irx1 have reciprocal interactions during cranial placode and otic vesicle formation

Sullivan, Caroline; Majumdar, Himani Datta; Neilson, Karen M.; Moody, Sally A.

doi:10.1016/j.ydbio.2018.12.003

Cited by 20 publications

(25 citation statements)

References 66 publications

(128 reference statements)

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“…3C,D,H). As previously reported (Sullivan et al, 2019), Six1WT-150 caused reduction of irx1 in the PPE, as did V17E, albeit at a significantly higher frequency (Fig. 3I).…”

Section: Six1 Mutants Alter Craniofacial Gene Expressionsupporting

confidence: 88%

“…As previously reported, in most cases, Six1WT-150 expanded the PPE expression of sox11 (Sullivan et al, 2019) (Fig. 3A,H).…”

Section: Six1 Mutants Alter Craniofacial Gene Expressionsupporting

confidence: 88%

“…Because we found that V17E mRNA caused early lethality at >150 pg/blastomere, its effects were compared to 150 pg/blastomere of Six1WT mRNA (Six1WT-150). The other Six1 mutants, which did not cause lethality, were expressed at 400 pg/blastomere and compared to 400 pg/blastomere of Six1WT mRNA (Six1WT-400), a dose used in numerous previous publications to determine the early developmental function of Six1 (Brugmann et al, 2004;Schlosser et al, 2008;Sullivan et al, 2019). Expression of either mutant or WT Six1 caused variable changes in gene expression (reduced, broader or no change) in nearly every batch of embryos; we report the frequency of each phenotype for every gene assayed in the graphs in Figs 2-4.…”

Section: Six1 Mutants Alter Craniofacial Gene Expressionmentioning

confidence: 99%

“…To accomplish this, we made four of the human mutations in Xenopus Six1 and expressed the mutant proteins on one side of embryos to assess their effects on the expression of a large number of genes that are required for the development of precursors of the tissues affected in BOS/BOR: the neural crest, PPE and otic placode. Several studies have shown that expressing Six1WT in embryos causes changes in early ectodermal gene expression (Brugmann et al, 2004;Schlosser and Ahrens, 2004;Christophorou et al, 2009;Schlosser et al, 2008;Sullivan et al, 2019). To determine whether the mutant Six1 proteins have a different effect on gene expression from Six1WT, we compared the frequency of gene expression changes (determined by comparing to the control side of the same embryo) caused by each manipulation.…”

Section: Effects On Craniofacial Gene Expressionmentioning

confidence: 99%

“…Studies in several vertebrates indicate that Six1 is a crucial regulator of cranial placode development (Brugmann and Moody, 2005;Grocott et al, 2012;Moody and LaMantia, 2015;Moody and Saint-Jeannet, 2014;Saint-Jeannet and Moody, 2014;Schlosser, 2006Schlosser, , 2010Streit, 2007). Six1 loss-of-function studies demonstrate reduced expression of several placode genes and defects in otic development, including loss of hair cells and defective patterning of the sensory epithelium in which they reside (Laclef et al, 2003;Zheng et al, 2003;Brugmann et al, 2004;Ozaki et al, 2004;Schlosser and Ahrens, 2004;Zou et al, 2004;Bricaud and Collazo, 2006;Konishi et al, 2006;Ikeda et al, 2007;Chen et al, 2009;Christophorou et al, 2009;Ikeda et al, 2010;Bricaud and Collazo, 2011;Zhang et al, 2017;Sullivan et al, 2019). Six1 gain of function expands placode domains at the expense of the adjacent epidermal and neural crest regions (Brugmann et al, 2004;Schlosser et al, 2008;Christophorou et al, 2009;Maharana and Schlosser, 2018), and promotes utricular hair cell over VIIIg neuron formation (Bricaud and Collazo, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development

Shah

Krohn

Baxi

et al. 2020

Disease Models &Amp; Mechanisms

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Single-nucleotide mutations in human SIX1 result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchiooto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within affected members of the same family, make it difficult to functionally distinguish between the different SIX1 mutations. We made four of the BOS/BOR substitutions in the Xenopus Six1 protein (V17E, R110W, W122R, Y129C), which is 100% identical to human in both the protein-protein interaction domain and the homeodomain, and expressed them in embryos to determine whether they cause differential changes in early craniofacial gene expression, otic gene expression or otic morphology. We confirmed that, similar to the human mutants, all four mutant Xenopus Six1 proteins access the nucleus but are transcriptionally deficient. Analysis of craniofacial gene expression showed that each mutant causes specific, often different and highly variable disruptions in the size of the domains of neural border zone, neural crest and pre-placodal ectoderm genes. Each mutant also had differential effects on genes that pattern the otic vesicle. Assessment of the tadpole inner ear demonstrated that while the auditory and vestibular structures formed, the volume of the otic cartilaginous capsule, otoliths, lumen and a subset of the hair cell-containing sensory patches were reduced. This detailed description of the effects of BOS/BOR-associated SIX1 mutations in the embryo indicates that each causes subtle changes in gene expression in the embryonic ectoderm and otocyst, leading to inner ear morphological anomalies.

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“…3C,D,H). As previously reported (Sullivan et al, 2019), Six1WT-150 caused reduction of irx1 in the PPE, as did V17E, albeit at a significantly higher frequency (Fig. 3I).…”

Section: Six1 Mutants Alter Craniofacial Gene Expressionsupporting

confidence: 88%

“…As previously reported, in most cases, Six1WT-150 expanded the PPE expression of sox11 (Sullivan et al, 2019) (Fig. 3A,H).…”

Section: Six1 Mutants Alter Craniofacial Gene Expressionsupporting

confidence: 88%

Section: Six1 Mutants Alter Craniofacial Gene Expressionmentioning

confidence: 99%

Section: Effects On Craniofacial Gene Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development

Shah

Krohn

Baxi

et al. 2020

Disease Models &Amp; Mechanisms

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Generation of a new six1‐null line in Xenopus tropicalis for study of development and congenital disease

Coppenrath

Tavares

Shaidani

et al. 2021

Genesis

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The vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors plays critical roles in the development of several organs. Six1 plays a central role in cranial placode development, including the precursor tissues of the inner ear, as well as other cranial sensory organs and the kidney. In humans, mutations in SIX1 underlie some cases of Branchio-oto-renal (BOR) syndrome, which is characterized by moderate-to-severe hearing loss. We utilized CRISPR/Cas9 technology to establish a six1 mutant line in Xenopus tropicalis that is available to the research community. We demonstrate that at larval stages, the six1-null animals show severe disruptions in gene expression of putative Six1 target genes in the otic vesicle, cranial ganglia, branchial arch, and neural tube. At tadpole stages, six1-null animals display dysmorphic Meckel's, ceratohyal, and otic capsule cartilage morphology. This mutant line will be of value for the study of the development of several organs as well as congenital syndromes that involve these tissues.

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Using Xenopus to discover new candidate genes involved in BOR and other congenital hearing loss syndromes

Neal,

Rajasekaran,

Jusić

et al. 2023

J Exp Zool Pt B

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Hearing in infants is essential for brain development, acquisition of verbal language skills, and development of social interactions. Therefore, it is important to diagnose hearing loss soon after birth so that interventions can be provided as early as possible. Most newborns in the United States are screened for hearing deficits and commercially available next‐generation sequencing hearing loss panels often can identify the causative gene, which may also identify congenital defects in other organs. One of the most prevalent autosomal dominant congenital hearing loss syndromes is branchio‐oto‐renal syndrome (BOR), which also presents with defects in craniofacial structures and the kidney. Currently, mutations in three genes, SIX1, SIX5, and EYA1, are known to be causative in about half of the BOR patients that have been tested. To uncover new candidate genes that could be added to congenital hearing loss genetic screens, we have combined the power of Drosophila mutants and protein biochemical assays with the embryological advantages of Xenopus, a key aquatic animal model with a high level of genomic similarity to human, to identify potential Six1 transcriptional targets and interacting proteins that play a role during otic development. We review our transcriptomic, yeast 2‐hybrid, and proteomic approaches that have revealed a large number of new candidates. We also discuss how we have begun to identify how Six1 and co‐factors interact to direct developmental events necessary for normal otic development.

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Six1 and Irx1 have reciprocal interactions during cranial placode and otic vesicle formation

Cited by 20 publications

References 66 publications

Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development

Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development

Generation of a new six1‐null line in Xenopus tropicalis for study of development and congenital disease

Using Xenopus to discover new candidate genes involved in BOR and other congenital hearing loss syndromes

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