BAR HARBOR -- Genetic research conducted at The Jackson Laboratory has identified a protein in mice that may play a fundamental role in the critical process of "wiring" the central nervous system during vertebrate embryonic development.
The abnormalities observed in mouse models bred at the Laboratory with mutations in the rcm (rostral cerebellar malformation) gene involve significant disruption of neuronal migration during development of the brain. Such genetic mutations in human brain development are known to result in disorders including epilepsy and severe mental retardation.
The study -- led by Susan L. Ackerman, Research Scientist at The Jackson Laboratory -- is reported in the April 24 issue of the journal Nature under the title, "The Mouse Rostral Cerebellar Malformation Gene Encodes an UNC-5 like Protein." Co-authors are Leslie P. Kozak, Stefan A. Przyborski, and Barbara B. Knowles, all of The Jackson Laboratory; and Laurie A. Rund, University of Illinois, Urbana, and Bert B. Boyer, University of Alaska, Fairbanks, both formerly of the Laboratory.
"This will have an impact on our understanding of how the human brain develops," says Dr. Ackerman. "This mouse mutant is unique in that it has cerebellar neurons in a completely different region of the brain. Our results support a fundamental role for the rcm protein in critical migratory events during cerebellar development."
Research in mice and other animals has shed light on the complex process of central nervous system development. Billions of neurons from "nurseries" deep within the brain are born and differentiated at specific times and migrate to precise locations in the central nervous system, where they are wired into the intricate circuit that assures the proper functioning of the brain.
But sometimes the migratory process goes astray, with neurons failing to reach the proper destinations and instead forming jumbled-up concentrations in other regions of the brain. In humans, this can result in conditions such as lissencephaly, or "smooth brain," in which the cerebral cortex lacks the normal surface texture. Lissencephalic children seldom survive, suffering severe mental retardation and seizures from birth.
The scientists report in Nature that the rcm mouse exhibits a dramatic reduction in cerebellar size and in cerebellar folding; that ectopic cerebellar cells are present in midbrain regions by three days after birth; and that postnatal cerebellar neuronal migration abnormalities are present. The mouse is also ataxic, or stumbling, in its gait.
The rcm gene is a member of a newly described family of vertebrate homologues of unc-5 (uncoordinated), a protein that has been found to be essential for normal cell migration during the development of the worm, C. elegans, which suggests an evolutionary conservation of gene function between invertebrates and mammals.