THE LABORATORY OF MAMMALIAN GENES AND DEVELOPMENT
Heiner Westphal, MD, Chief

 
The Laboratory of Mammalian Genes and Development (LMGD) generates gene-altered mice to study pattern formation, T cell development, and genomic imprinting. The mutant mice also serve as paradigms for human genetic disorders.  

Heiner Westphal leads the Section on Mammalian Molecular Genetics, which carries out functional analyses of genes that control key steps of post-implantation development in the mammalian embryo. Transcription factors are major players in the cascade of molecular events that implement the body plan. The section uses a loss-of-function approach to study the function of the LIM/homeodomain (Lhx) class of transcription factors and of factors that mediate their action. Recently, the group discovered that development of cholinergic neurons in the ventral telencephalon is severely impaired in mice lacking a functional Lhx8gene. The loss of telencephalic cholinergic projection neurons is a hallmark of neurodegenerative disorders such as Alzheimer's disease and is likely to play a role in the cognitive impairments of such patients. For this reason, the Lhx8null mutant mouse constitutes a valuable model for functional studies of cholinergic projection neurons in the context of memory and cognition.
 

Led by Paul Love, the Section on Cellular and Developmental Biology focuses on T lymphocyte development, with special emphasis on the role of signal transduction molecules and pathways. Recent studies identified a critical role for the lymphocyte adapter protein LAT in transmitting signals from the cell surface to downstream pathways that control T cell maturation and function. These studies also demonstrated that coordination of lymphocyte signaling responses is essential for preventing inappropriate cell proliferation. In another study, researchers discovered a difference in the subunit composition of the signal-transducing antigen receptor complexes (TCRs) expressed on the two different lineages of T lymphocytes, alpha/beta and gamma/delta T cells. The data suggest that different TCR structures may influence the activation kinetics and functional responses of distinct T cell lineages. A third study, centering on the molecules that control T cell migration and trafficking, revealed a role for the chemokine receptor CCR9 in regulating T cell migration within the thymus during development.
 

Under the direction of Karl Pfeifer, the Section on Genomic Imprinting focuses on the regulated expression and biological function of a cluster of genes on the distal end of mouse chromosome 7. The genes share an unusual form of transcriptional regulation, genomic imprinting, that is specific to mammals. Imprinted genes are expressed from only one chromosome in a parent-of-origin-dependent manner. The section has identified a small cis-acting element whose epigenetic modification, established during gametogenesis, is responsible for marking the parental origin of this chromosomal region. Later, the presence of these modifications drives a developmental program that induces further changes that then cause allele-specific expression. The organization and regulated expression of the genes in this cluster are well conserved in humans, and mutations in the human genes are associated with developmental disorders, several types of tumors, and cardiac arrhythmias. The section has successfully developed a mouse model for the heart condition and has demonstrated that the cardiac deficiency is specifically attributable to the inability of the animals to respond to beta-adrenergic-mediated stress.