Yale Zebrafish Research Core

The Yale Zebrafish Research Core (YZRC) was founded with two goals. First, to model human diseases in zebrafish with the long-term goal of facilitating small molecule screens for novel therapies. Second, to lower the barrier of entry for Yale investigators seeking to carry out experiments in zebrafish.

Why Zebrafish?

Zebrafish possess many advantages over other model systems. They are optically transparent throughout much of early development, greatly facilitating live imaging studies. The zebrafish genome is of excellent quality and fish-specific transgenic tools are very mature and efficient. Thousands of zebrafish can be generated by a single crossing, and the resultant larvae are fully active, behaving vertebrate organisms within days of fertilization. Zebrafish larvae are also small enough to fit happily into a 96-well plate format. Taken together, these factors make zebrafish a uniquely powerful model for performing chemical or genetic screens.

Disease Modeling

Cardiovascular disease

A human patient population prone to intracranial hemorrhages was identified and exome-sequenced by Yale researchers. A candidate mutation was introduced into zebrafish; this was sufficient to generate hemorrhages and necrosis in larval zebrafish (arrowheads).

Cancer

Pigment cells are derived from a transient embryonic cell type known as the neural crest. Mutations in receptor tyrosine kinase signaling have been shown to influence cell fate acquisition, resulting in pigment and organ development phenotypes (see figure to the right showing the pigment phenotype). Recently, Yale researchers identified novel ligands of the Ltk receptor tyrosine kinase known as Augmentors. Mutations in these Augmentor genes also generate pigment phenotypes. Understanding signaling in pigment cells has critical relevance to disease—a melanoma model generated in fish that closely resembles human melanoma has been shown to recapitulate aspects of neural crest development.

Meningitis

In humans, bacterial meningitis causes headaches, fever, seizures, and neck stiffness. Many of these symptoms are replicated in a zebrafish model of the disease in which Streptococcus pneumoniae is injected into the hindbrain ventricle. Neurons in contact with the cerebrospinal fluid respond to bitter-tasting metabolites secreted by bacteria, and this response can be monitored in vivo in real-time using genetically-encoded calcium indicators.

Rare and congenital diseases

Several zebrafish mutants have been identified which exhibit progressively worsening scoliosis. Rescuing the function of particular genes (in this case ptk7) is sufficient to rescue scoliotic phenotypes. Human patients with idiopathic scoliosis have also been found to carry missense mutations in the ptk7 gene.