"This work describes the function of a gene that controls the assembly of a brain structure crucial for high order mental functions," said NICHD Director Duane Alexander, MD. "The discovery provides crucial insight into understanding the complex molecular basis of hippocampus development. Efforts of this nature may one day lead to treatments of hereditary brain disorders that affect the hippocampus."
The gene, termed Lhx5, is a member of the family of genes known as the LIM Homeobox genes, noted Dr. Westphal. Homeobox genes have changed little during the course of evolution and seem to fulfill similar functions, from roundworm to man. Essentially, these genes pave the way for developing embryo cells to later form organs and tissues.
To conduct their experiment, the researchers used a procedure known as gene knockout to inactivate the Lhx5 gene in the mouse, Dr. Westphal explained. They found that embryos lacking Lhx5 function developed a malformed hippocampus. For this brain structure to develop normally, cells must first migrate to the correct position in the developing brain and then form the precisely ordered tissue layers of the hippocampus. In the Lhx5 knockout embryos, cells failed to migrate normally, and this resulted in a grossly distorted structure in which regular cell layers could no longer be recognized. Dr. Westphal said the layers in the normal hippocampus are analogous to patterns in the layers, or strata, seen in exposed rock formations.
"The malformation is like rock strata where some cataclysmic event has mixed up the deposits so that you no longer see any discernible layers," said Dr. Westphal.
Lhx5 knockout mice provide an exciting model to study in detail how this gene acts and how its inactivation affects hippocampus assembly and function, he added. This work is part of a concerted effort to unravel molecular mechanisms that underlie complex brain function, an effort currently under way in many laboratories.