<i>wnt16</i> regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome

Watson, Claire J.; de, Ernesto Morfin Montes; Fiedler, Imke A.K.; Cronrath, Andrea R; Callies, LuLu K.; Swearer, Avery Angell; Sethuraman, Visali; Ahmed, Ali R.; Monstad-Rios, Adrian T.; Rojas, Maria F; Tang, Weiliang; Gardiner, Edith M.; Busse, Björn; Hsu, Yi‐Hsiang; Kwon, Ronald Y.

doi:10.1101/2021.08.12.456120

Cited by 3 publications

(3 citation statements)

References 117 publications

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“…To generate efemp1 mutant alleles, we performed CRISPR-Cas9 gene editing as previously described (Watson et al 2020;Watson et al 2022). We used a guide RNA (gRNA, Alt-R system, Integrated DNA Technologies) targeting exon 4 of efemp1 complexed with Cas9 protein (HiFi 3xNLS-Cas9, IDT).…”

Section: Crispr-based Gene Editingmentioning

confidence: 99%

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Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

Gómez,

Alvarado,

Yase

et al. 2024

Preprint

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Heritable Disorders of Connective Tissues (HDCT) are a heterogenous, pleiotropic group of conditions that broadly affect connective tissues.EFEMP1is a member of the fibulin family of extracellular matrix (ECM) glycoproteins which is expressed in various human tissues. Individuals withEFEMP1variants have recently been identified and appear to have Marfan-like characteristics. Clinical phenotypes of these individuals include hernias, advanced bone age, tall stature, myopia, joint laxity, and thin skin.EFEMP1-associated HDCTs have been identified in individuals with biallelic and monoallelic variants. There is an urgent need to better understand the role ofEFEMP1in regulating connective tissues including bone, and the pathophysiological mechanisms underlying the spectrum of genotype-phenotype relationships seen in EFEMP1-associated HDCTs. To investigate the role ofEFEMP1in developing and adult bone, we used CRISPR-based editing to generate two efemp1 zebrafish alleles encoding for premature termination codons (PTCs) predicted to delete or severely alter the fibulin-type domain. Both alleles exhibited similar phenotypes in juvenile and adult fish. In juvenile fish, we did not identify changes in body size or vertebral development. In adults, we found significant changes in body length, bone microarchitecture, and craniofacial measurements in both heterozygous and homozygous mutant fish. These results expand our understanding of the role ofefemp1in the skeleton and highlight the potential for dominant nonsense variants to play a role in manifestation of clinical phenotypes inEFEMP1-associated HDCTs.

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Section: Crispr-based Gene Editingmentioning

confidence: 99%

“…Calcein labeling and imaging was performed as described previously (Watson et al 2022). 13dpf larvae were stained with a 0.2% calcein (Sigma) solution in fish water for 20 minutes followed by 3x 10-minute washes in fish water.…”

Section: Vertebral Mineralization Analysismentioning

confidence: 99%

Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

Gómez,

Alvarado,

Yase

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…The same group performed RNA-seq, identifying differentially expressed genes associated with mTOR, FoxO and VEGF pathways [ 96 ]. Finally, recent work by Watson et al interrogated the biology behind the pleiotropy at the locus (which was associated with BMD and lean mass) [ 97 ]. The authors detected reduced vertebral centra volume and length, and the fish were shorter.…”

Section: Zebrafish As Animal Models To Accelerate Discoveries Of Huma...mentioning

confidence: 99%

Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models

Kague

Karasik

2022

Genes

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The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish (Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.

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Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases

Diamond

Burtner

Siddiqui

et al. 2022

Preprint

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Genetic diseases affecting the skeletal system present with a wide range of symptoms that make diagnosis and treatment difficult. Genome-wide association and sequencing studies have identified genes linked to human skeletal diseases. Gene editing of zebrafish models allows researchers to further examine the link between genotype and phenotype, with the long-term goal of improving diagnosis and treatment. While current automated tools enable rapid and in-depth phenotyping of the axial skeleton, characterizing the effects of mutations on the craniofacial skeleton has been more challenging. The objective of this study was to evaluate a semi-automated screening tool can be used to quantify craniofacial variations in zebrafish models using four genes that have been associated with human skeletal diseases (meox1, plod2, sost, and wnt16) as test cases. We used traditional landmarks to ground truth our dataset and pseudolandmarks to quantify variation across the 3D cranial skeleton between the groups (somatic crispant, germline mutant, and control fish). The proposed pipeline identified variation between the crispant or mutant fish and control fish for four genes. Variation in phenotypes parallel human craniofacial symptoms for two of the four genes tested. This study demonstrates the potential as well as the limitations of our pipeline as a screening tool to examine multi-dimensional phenotypes associated with the zebrafish craniofacial skeleton.

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wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome

Cited by 3 publications

References 117 publications

Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models

Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases

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