Genetic interactions support an inhibitory relationship between bone morphogenetic protein 2 and netrin 1 during semicircular canal formation

Hwang, Chan Ho; Keller, James E.; Renner, C.; Ohta, Sho; Wu, Doris K.

doi:10.1242/dev.174748

Cited by 11 publications

(11 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BMP2 (bone morphogenetic protein 2), a member of the transforming growth factor-beta (TGF-β) superfamily, possesses crucial functions in developmental processes, including cardiogenesis, digit apoptosis, somite formation, neuronal growth, and musculoskeletal development ( Schlange et al, 2000 ; Benavente et al, 2012 ; Christen et al, 2012 ; Gámez et al, 2013 ). As mentioned in a literature review, BMP2 plays a crucial role in the formation of three semicircular canals during inner ear development ( Hwang et al, 2019 ). The otic-specific knockout of Bmp2 caused the lack of all semicircular canals in a mouse model ( Hwang et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Wen

Song

Bai

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Waardenburg syndrome (WS) is an autosomal dominant inherited disorder that is characterized by sensorineural hearing loss and abnormal pigmentation. SOX10 is one of its main pathogenicity genes. The generation of patient-specific induced pluripotent stem cells (iPSCs) is an efficient means to investigate the mechanisms of inherited human disease. In our work, we set up an iPSC line derived from a WS patient with SOX10 mutation and differentiated into neural crest cells (NCCs), a key cell type involved in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. After that, we carried out high-throughput RNA-seq and evaluated the transcriptional misregulation at every stage. Transcriptome analysis of differentiated NCCs showed widespread gene expression alterations, and the differentially expressed genes (DEGs) were enriched in gene ontology terms of neuron migration, skeletal system development, and multicellular organism development, indicating that SOX10 has a pivotal part in the differentiation of NCCs. It’s worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes connected to the inner ear morphogenesis. Based on the protein-protein interaction network, we chose four candidate genes that could be regulated by SOX10 in inner ear development, namely, BMP2, LGR5, GBX2, and GATA3. In conclusion, SOX10 deficiency in this WS subject had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. The DEGs most significantly enriched in inner ear development and morphogenesis may assist in identifying the underlying basis for the inner ear malformation in subjects with WS.

show abstract

Section: Discussionmentioning

confidence: 99%

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Wen

Song

Bai

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…12 BMP2 is also expressed during the development of the inner ear, and an ear-specific knockout of BMP2 leads to the lack of all 3 semicircular canals in the cochlear structure. 13 Therefore, the motion sickness and poor ability to sense the direction of sound in the twin sisters may be related to the cochlear dysplasia caused by BMP2 mutation.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing Identifies Two Novel Rare Mutations in BMP5 and BMP2 in Monozygotic Twins With Microtia

Liu

Wang

Guo

et al. 2021

Journal of Craniofacial Surgery

View full text Add to dashboard Cite

Microtia is a rare congenital anomaly of the ear; it is regulated by both genetic and environmental factors. However, the mechanisms underlying its pathogenesis are unknown. In this study, the genomes of 2-year-old twin sisters with right microtia were sequenced using human genome-wide sequencing, an approach useful for identifying mutations in genes responsible for congenital microtia. The phenotypes of the twin sisters included congenital microtia on the right side, abnormal auricle shape in the right external ear, a peanut shape for the residual ear, and complete atresia of the right external auditory canal. In the twin sisters, we identified a previously unknown mutation in BMP5(exon4:c.833-4C>G), as well as a new mutation (exon2:c.G332T:p.S111I) in BMP2, both of which were confirmed using polymerase chain reaction-based amplification of the corresponding genome regions, followed by first-generation sequencing. The exon4:c.833-4C>G mutation in human BMP5 may be the main cause of microtia in the twin sisters. A pathogenic mutation in human BMP2 (exon2:c.G332T:p.S111I) may be responsible for the facial deformity in the twin sisters. Thus, our study demonstrates the potential of genome-wide sequencing for identifying novel mutations associated with microtia on the whole-genome scale and extends the mutation spectrum of BMP5. Additionally, our data suggest that BMP2 is another pathogenic gene associated with microtia.

show abstract

“…BMP signalling is known to play an important role in semicircular canal formation in mice, chick and zebrafish (reviewed in (Alsina and Whitfield, 2017)). Our previous work demonstrated a requirement for Bmp2b function in the development of all three semicircular canal ducts in the zebrafish ear (Hammond et al, 2009), and this requirement is conserved in mice (Hwang et al, 2019). The bmper mutant phenotype is more specific and less severe than that in bmp2b mutants, only affecting the anterior and posterior ducts, and resulting in dorsal truncations of these structures in the adult ear.…”

Section: Zygotic Bmper Function Is Required For Correct Morphogenesis Of the Anterior And Posterior Semicircular Canal Ducts In The Develmentioning

confidence: 94%

Bmper is required for morphogenesis of the anterior and posterior semicircular canal ducts in the developing zebrafish inner ear

Baxendale

et al. 2021

Preprint

View full text Add to dashboard Cite

BMP signalling is known to have a conserved function in development of the semicircular canal system of the vertebrate inner ear, but its regulation, target genes and effects on cell behaviour during otic morphogenesis are not fully understood. We have characterised the effects of mutations in the zebrafish gene bmper, which codes for a regulator of BMP signalling with both pro- and anti-BMP roles in different developmental contexts. The inner ears of bmper mutant embryos develop with truncations of the anterior and posterior semicircular canal ducts. To image the developing ear in live embryos, we have exploited a new transgenic line, Tg(smad6b:EGFP), which exhibits strong GFP expression in the otic epithelium. Morphometric analysis indicates defects in the bmper mutant ear from early stages of semicircular canal formation, correlating with a specific reduction in BMP signalling activity and specific loss of dlx5a expression in dorsal otic epithelium. Subsequent changes to cell shape occur at the truncation site and the dorsolateral septum. The bmper mutations that we describe are adult viable; truncation of the anterior and posterior semicircular canal ducts persists into adulthood. Our results argue against a major role for Bmper in specification of the pre-placodal region, induction of the otic placode, or development of the neural crest, processes in which Bmper function has previously been implicated. Instead, we conclude that a key requirement for Bmper function in the zebrafish is to promote BMP signalling during patterning and morphogenesis of the semicircular canal system.

show abstract

Genetic interactions support an inhibitory relationship between bone morphogenetic protein 2 and netrin 1 during semicircular canal formation

Cited by 11 publications

References 38 publications

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Whole-Genome Sequencing Identifies Two Novel Rare Mutations in BMP5 and BMP2 in Monozygotic Twins With Microtia

Bmper is required for morphogenesis of the anterior and posterior semicircular canal ducts in the developing zebrafish inner ear

Contact Info

Product

Resources

About