Evidence Mounts Against Mainstream Dogma In Embryology, Could Shed New Light On Neurological Defects

A group of scientists at the Carnegie Institution of Washington, Vanderbilt University, and the National University of Singapore bring forth more evidence in opposition to the classic model with their report appearing in the September 10 Nature. The authors argue that the first steps in floor plate development occur earlier than was initially thought, in reaction to inducing factors other than those emitted by the notochord. The new data, based on studies of zebrafish mutants, may also shed light on certain neurological defects that affect humans as well as fish‹ namely, holoprosencephaly. This syndrome, which can result in severe deformity and death, prevents the forebrain hemispheres from separating normally, in turn preventing the initial eye field from separating into two eyes during embryonic development.

The model

The mainstream model for patterning of the central nervous system was demonstrated in the 1980s and much supportive evidence has been obtained ever since. In this model, the notochord instructs neural tube precursor cells to differentiate into floor plate during the early stages of somitogenesis (i.e., the time of formation of somites, blocks of similar cells that differentiate into muscles, bone, and other tissues). The command arrives via a potent messenger protein, Sonic hedgehog. Once formed, the floor plate then induces motor neurons to develop on either side (motor neurons will ultimately relay information between the spinal cord and muscles).

The challenge

The Nature paper poses challenges to both the timing of floor plate induction and the central role of Hedgehog proteins. In earlier experiments, Marnie Halpern, an embryologist at the Carnegie Institution of Washington and a co-author of the paper, reported that floor plate can differentiate in the absence of the notochord. Conversely, in some zebrafish mutants, floor plate does not always form despite the presence of the Sonic hedgehog signal. These mutants lack a gene called cyclops. According to the newpaper, cyclops has been found to encode another type of intercellular signaling molecule that plays a key role in floor plate and brain development. Cyclops is expressed during gastrulation, long before somitogenesis. Gastrulation is the developmental stage at which an embryo first forms its germ layers: the endoderm, mesoderm, and ectoderm. (Germ layers give rise to various organs later in development.)

cyclops: the gene

The authors founds that the zebrafish cyclops gene resembles the nodal gene of mouse and related genes in the frog, all of which are powerful instigators of mesoderm development. Cyclops is expressed during gastrulation in mesendoderm, in both the head and posterior tailbud. It disappears from these regions, however, as somites begin to form. Experimentation with the gene revealed that the cyclops gene product is a potent regulator of cell fates in embryonic tissues. Cyclops, the researchers argue, is crucial during the gastrulation stage for mediating an early signaling pathway for ventral brain and floor plate differentiation. Rather than respond to signals arising solely from the notochord, the floor plate may actually develop from the same precursor cells that give rise to the notochord itself. The role of Hedgehog signaling in this process and its relationship to Cyclops-mediated signaling remains to be determined.

Cyclopia: the defect

Cyclops also provides signals required for correct development of the mesendoderm, which produces a tissue (prechordal plate) that patterns the ventral forebrain and separates the initial eye field into bilateral eyes. Failure of these processes results in a reduced forebrain and cyclopia (fused eyes). Cyclopia appears not only in animals such as the zebrafish, but also in humans who develop a syndrome called holoprosencephaly. Some cases of holoprosencephaly have been found to result from mutations of the human sonic hedgehog gene. However, other chromosomal regions, including as yet unidentified genes, also produce very similar birth defects. For this reason, scientists are eager to learn more about the precise role of the human equivalent of the zebrafish cyclops gene in patterning the developing embryo's nervous system.