Scientist: Research Projects: Research Articles
Zebrafish as a Model for Craniofacial Malformations Associated
with Fetal Alcohol Syndrome:
In vertebrate embryos, the formation of the structures of the head
is a complex process for which we have few molecular details, especially
regarding the contribution of the neural crest. The neural crest
is a transient structure composed of cells that migrate extensively
throughout the embryo and contribute to a number of organs. The
control of crest cell morphogenesis is critical to the embryo, in
as much as abnormal neural crest migration or proliferation results
in a number of serious human disorders ranging from cleft palate
to frontonasal dysplasia.
The long term goal of Dr. Laura Roman's laboratory of the Center
for Craniofacial Development and Disorders at Johns Hopkins University
is to define factors controlling normal craniofacial development.
While other vertebrate systems have provided insight into some of
the key steps in neural crest cell morphogenesis, these studies
have been limited by the complexities of these organisms and the
inaccessibility of embryonic tissues. Her laboratory proposes to
use zebrafish as a model organism in which to study the effects
of ethanol on the neural crest cell populations that contribute
to the structures of the face.
There are a number of features of zebrafish embryogenesis which
make them an attractive system in which to study the molecular mechanism
underlying the malformations seen in children in Fetal Alcohol Syndrome.
First, fertilization is external so that all stages of embryogenesis
are accessible, and thus independent of the physiological status
of the mother. Second, the embryos are transparent, permitting the
visualization of individual migratory cells in the living embryo.
Third, zebrafish craniofacial development, like that in humans,
is sensitive to teratogens like ethanol and retinoic acid.
Dr. Roman's laboratory has identified and cloned two markers (rtp1
and rtp) for subpopulations of cranial neural crest cells that contribute
to developing craniofacial structures. They have obtained preliminary
results which indicate that exposure of zebrafish embryos to the
same levels of alcohol known to cause malformations in human fetuses,
results in midline, ocular and cardiac defects in zebrafish. They
have also demonstrated that several of the molecular and biochemical
pathways affected by ethanol in other vertebrates, are also altered
in zebrafish. Through the use of zebrafish as model system for fetal
alcohol syndrome, we will be able to gain molecular insights as
to how the critically balanced morphogenic events required for craniofacial
development are disrupted by ethanol.
Effects of ethanol on zebrafish craniofacial development. Zebrafish
embryos were exposed to 30 mM ethanol at gastrulation. This concentration
of alcohol has been shown to induce fetal alcohol syndrome in humans.
(A and C) Five day old embryos exhibit a shortening
of the trunk and cardiac and craniofacial malformations. Pronounced
ocular and midline defects were observed, and the jaw was hypoplastic.
Similar defects are seen in children with fetal alcohol syndrome.
(B and D) Age-matched control. Alcian blue staining
of the skeleton revealed that the neural crest derivatives of the
first (blue) and second (yellow) arches were affected in ethanol
treated embryos (E and G). Note that the basihyal
(bh) bone is missing in the treated embryos, and the structure of
the hyosympletic (hs), basihyal (bh), palatoquadrate (pq), and ethmoid
plate (e) is aberrant (E and G) relative to the control
(D-H).
Author: Laura Roman, Ph.D.
Date: September 28, 1998
Last Updated:
6/27/02
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