Zebrafish Provide Knock-out Model for Study of FOP Gene

Cells from the blood and from the dental pulp have been
invaluable in studying FOP, but animal models of human disease
provide the possibility of studying the developmental effects and
implications of genetic diseases that are impossible to study in cell
culture. The tiny zebrafish is an extremely valuable animal model
for studying the effects of BMP signaling during development.
Importantly, zebrafish development occurs externally and can be
monitored under laboratory conditions. As in humans, zebrafish
have two copies of ACVR1, the FOP gene. The world's expert
on the ACVR1 gene in zebrafish, Dr. Mary Mullins, a Professor
of Developmental Biology, is at the University of Pennsylvania,
a serendipitous occurrence that facilitates close collaborative
interactions with the FOP Core laboratory.

Zebra Fish


When both copies of the ACVR1 gene are knocked-out or removed
from the zebrafish embryo, severe developmental malformations
occur due to the absence of BMP signaling from the ACVR1
receptor. Microinjection of messenger RNA encoded by the
normal human ACVR1 gene into the zebrafish embryo partially
rescues the developmental abnormality. However,
microinjection of RNA encoded by the mutant FOP gene into
the zebrafish embryo over-corrects the ACVR1 deficiency. These
important experiments, conducted in collaboration with Dr.
Mullins' laboratory, demonstrate that the mutant FOP gene is
overactive in a living experimental animal during development.
These experiments are vitally important not only in elucidating
the developmental effects of the FOP gene mutation, but also in
screening large pharmaceutical libraries for compounds that can
block overactive BMP signaling in a living organism, as we will
see later in this report. These data provide the first experimental
evidence that the FOP gene is overactive within the cells and tissues
of a living organism.