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

Abstract

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.

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

“…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.…”

Deep learning is widely applicable to phenotyping embryonic development and disease

“…These investigations allowed us to accurately pinpoint abnormalities of the anterior craniofacial elements, specifically the Meckel's and ceratohyal cartilage. The ability to generate high-resolution 3D reconstructions of this model will facilitate further studies into genetic or chemical modifiers of six1 -related branchio-oto-renal syndrome ( Tavares et al, 2021 ).…”

Retinal determination gene networks: from biological functions to therapeutic strategies

“…Inhibit cell proliferation, stemness and tumorigenesis [17] Inhibit the expression of Wnt signaling downstream targets (c-Myc and cyclinD1) Suppress CRC growth [18] Inhibit TGF-β signaling Inhibit migration and invasion of CRC [19] BC Down-regulating the transcription of MMP-9 Inhibit BC cell invasion and metastasis [20] Inhibit the transcriptional activity of SNAI1 Repress breast carcinoma metastasis [21] Decrease the level of CD44 Suppress BC progression [22] Block YB-1 Represses YB-1-mediated oncogenic transcription and translation [23] Bind to p53 Inhibit BC contact-independent growth [24] Suppress IL-8 Inhibit BC cellular migration and invasion [8] Inhibit Moreover, mutations of SIX1 or EYA contribute to branchio-oto-renal (BOR) syndrome, muscle defects, asthma, etc. [59,94,95].…”

“…Moreover, mutations of SIX1 or EYA contribute to branchio-oto-renal (BOR) syndrome, muscle defects, asthma, etc. [ 59 , 94 , 95 ].…”

“…So-binding protein (Sobp) binds as a SIX1 cofactor and inhibits the transcriptional activation of SIX1 and EYA1, which changes the developmental process of ear follicles and leads to craniofacial cartilage defects. Therefore, Sobp was determined as a candidate gene for BOR syndrome and other deafness syndromes [ 94 ]. Sox 2+ proneurosensory progenitors within otic ectoderm form sensory cells and neurons for hearing.…”