Zebrafish Reveal Insights into Rare Bone Disorders

LaBonty and Yelick Spotlight

Pam Yelick and Melissa LaBonty with images of wild type and mutant fish

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BMP (bone morphogenetic protein) signaling is a highly evolutionarily conserved pathway involved in a number of developmental processes, including the formation of cartilage and bone. BMPs signal through a heteromeric complex of Type I and Type II BMP receptors, leading to the phosphorylation and activation of cytoplasmic Smad proteins, which subsequently translocate to the nucleus to activate transcription. Among other roles, Smad target genes promote the differentiation of mesenchymal stem cells into chondroblasts and osteoblasts.

For the past 20 plus years, the Yelick lab has identified and studied TGF-β/BMP superfamily receptors and their function in zebrafish. One such receptor, Acvr1l (previously called Alk8), was identified as a Type I TGF-β/BMP receptor family member based on its significant sequence homology to other TGF-β family receptors. Acvr1l is ubiquitously expressed during zebrafish embryonic development, and becomes more restricted in its expression at later developmental times. Functional characterization of Acvr1l in the embryo revealed a critical role in dorsoventral patterning, where expression of constitutively active (CA) Acvr1l mRNA produced ventralized embryos, and expression of dominant negative Acvr1l caused dorsalized phenotypes, both of which were early lethal.

Recently, it was discovered that activating mutations in the human homolog of zebrafish Acvr1l, ACVR1, are associated with Fibrodysplasia Ossificans Progressiva (FOP). This rare, autosomal dominant genetic disorder is characterized by the gradual heterotopic ossification (HO) of fibrous tissues, including skeletal muscle, tendons, and ligaments. FOP patients usually form HO by 7 years of age, experience progressively limited mobility into their teens as the fibrous tissues of their upper body ossify, and are wheel chair bound by their 30’s. The median age of survival is 40 years. FOP affects approximately 1 in every 2 million individuals, making it difficult to study the molecular mechanisms driving disease progression. Therefore, animal models are needed to elucidate the etiology and progression of human FOP.

Melissa LaBonty, a CMDB PhD candidate in the Yelick laboratory, is working to establish and characterize an adult zebrafish model for FOP. To avoid early lethal effects of embryonic CA Acvr1l expression, the Yelick lab generated transgenic zebrafish harboring heat-shock-inducible CA-Acvr1l, which ubiquitously express CA-Acvr1l only when exposed to the permissive temperature of 37°C. Melissa has characterized the development of a number of FOP-like symptoms in adult CA-Acvr1l-expressing zebrafish including HO, spinal lordosis, vertebral fusions, malformed pelvic fins, and upregulated BMP signaling. These results suggest that transgenic HS-CA-Acvr1l adult zebrafish can serve as a model to study FOP disease progression. Melissa now plans to use the zebrafish FOP model to identify cell lineages contributing to the HO in FOP zebrafish. In addition, she plans to use CA-Acvr1l-expressing zebrafish to identify novel therapeutics to treat human FOP.

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