Abnormal craniofacial and spinal bone development with<i>col2a1</i>a depletion in a zebrafish model of CHARGE syndrome

Breuer, Maximilian; Rummler, Maximilian; Zaouter, Charlotte; Willie, Bettina M.; Patten, Shunmoogum A.

doi:10.1101/2020.07.10.197533

Cited by 4 publications

(2 citation statements)

References 83 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we show a role for Chd7 in regulating col2a1 expression, a type II collagen and the major component of cartilage (55). Interestingly, regulation of col2a1 by Chd7 is also observed in zebrafish (73). While additional studies are required, we speculate that Chd7 could regulate col2a1 in a complex with the transcription factor Sox10 (74, 75) or through the TGF-β signaling pathway (35, 76).…”

Section: Discussionmentioning

confidence: 94%

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Jofré

Hoffman

Cervino

et al. 2021

Preprint

View full text Add to dashboard Cite

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. However, despite the public health relevance of this disorder, relevant targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of CHD7, is required for dauer morphogenesis, lifespan determination, and stress response. Genetic epistasis placed chd-7 in the TGF-β pathway. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the TGF-β pathway. Interestingly, DAF-12 transcriptionally upregulated chd-7, which is necessary to repress daf-9 for execution of the dauer program. Transcriptomic analysis comparing chd-7 defective and normal dauers showed enrichment of collagen genes, consistent with a conserved role for the TGF-β pathway in expression of the extracellular matrix. To validate a conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino mediated knockdown of Chd7 led to embryonic lethality, a reduction in col2a1 mRNA levels and craniofacial defects in tadpoles. Both lethality and malformations were partially rescued in Chd7-depleted embryos by over-expression of col2a1. We suggest that pathogenic features of CHARGE syndrome caused by Chd7 mutations, such as craniofacial malformations, result from the reduction of collagen levels. These studies establish C. elegans as an amenable animal model to study the etiology of the developmental defects associated with pathogenic Chd7.

show abstract

Section: Discussionmentioning

confidence: 94%

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Jofré

Hoffman

Cervino

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Ocular structural defects upon loss of Chd7 in other species have been broadly described but not rigorously investigated. Results of knockdown and knockout studies contain general descriptions of microphthalmia, coloboma, and anterior defects, but an in-depth understanding of mechanism or contribution of CHD7 to these defects is lacking (Jacobs-Mcdaniels and Albertson, 2011;Balow et al, 2013;Cloney et al, 2018;Liu et al, 2018;Liu and Liu, 2019;Breuer et al, 2020).…”

Section: Role Of Chd7 In Development Of Ocular Structuresmentioning

confidence: 99%

Eyes on CHARGE syndrome: Roles of CHD7 in ocular development

Krueger

Morris

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The development of the vertebrate visual system involves complex morphogenetic interactions of cells derived from multiple embryonic lineages. Disruptions in this process are associated with structural birth defects such as microphthalmia, anophthalmia, and coloboma (collectively referred to as MAC), and inherited retinal degenerative diseases such as retinitis pigmentosa and allied dystrophies. MAC and retinal degeneration are also observed in systemic congenital malformation syndromes. One important example is CHARGE syndrome, a genetic disorder characterized by coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Mutations in the gene encoding Chromodomain helicase DNA binding protein 7 (CHD7) cause the majority of CHARGE syndrome cases. However, the pathogenetic mechanisms that connect loss of CHD7 to the ocular complications observed in CHARGE syndrome have not been identified. In this review, we provide a general overview of ocular development and congenital disorders affecting the eye. This is followed by a comprehensive description of CHARGE syndrome, including discussion of the spectrum of ocular defects that have been described in this disorder. In addition, we discuss the current knowledge of CHD7 function and focus on its contributions to the development of ocular structures. Finally, we discuss outstanding gaps in our knowledge of the role of CHD7 in eye formation, and propose avenues of investigation to further our understanding of how CHD7 activity regulates ocular and retinal development.

show abstract

The CHARGE syndrome ortholog CHD-7 regulates TGF-β pathways in Caenorhabditis elegans

Jofré

Hoffman

Cervino

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance CHARGE syndrome is a complex developmental disorder caused by mutations in CHD7 (chromodomain helicase DNA-binding protein-7). We identified Caenorhabditis elegans chd-7 in a screen for suppressors of dauer formation, an alternative larval stage that develops under harsh environmental conditions. We found chd-7 regulates tumor growth factor-β (TGF-β) signaling pathways both for dauer diapause and for development of the cuticle, a specialized extracellular matrix. In frog embryos, Chd7 promotes Col2a1 expression, which is necessary and sufficient to prevent CHARGE features. These studies establish a conserved role for Chd7 from worms to vertebrates in regulating the TGF-β signaling pathway. Genetic dissection of chd-7 ’s role in C. elegans may help to define the molecular and cellular events that contribute to CHARGE syndrome.

show abstract

Abnormal craniofacial and spinal bone development withcol2a1a depletion in a zebrafish model of CHARGE syndrome

Cited by 4 publications

References 83 publications

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Eyes on CHARGE syndrome: Roles of CHD7 in ocular development

The CHARGE syndrome ortholog CHD-7 regulates TGF-β pathways in Caenorhabditis elegans

Contact Info

Product

Resources

About