The Laboratory of Mammalian Genes and Development 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. The laboratory comprises three independent research groups.

The Section on Mammalian Molecular Genetics, headed by Heiner Westphal, studies genes that regulate embryonic development. Currently, the section is focusing on LIM-domain–containing regulators of development and cofactors that bind to them. Details have emerged during the past year on two cofactors, termed Ldb1 and Ssdp. These gene products are essential for embryonic development and have been well preserved throughout invertebrate and vertebrate evolution. Gain- and loss-of-function studies in the mouse, Xenopus, and Drosophila have shown that Ldb1 and Ssdp mediate the action of a number of LIM factors that exert important controls during gastrulation and organogenesis.

The Section on Cellular and Developmental Biology, directed by Paul Love, focuses on the molecular genetics of T cell development, with special emphasis on genes that regulate signal transduction in developing and mature T cells. Recent studies revealed a critical role for the lymphocyte adaptor protein LAT in transmitting signals from the cell surface to downstream pathways that control T cell maturation and function. These experiments also demonstrated that coordination of lymphocyte signalling responses is essential to prevent abnormal cell proliferation. All mammals contain two lineages of T cells, alpha/beta and gamma/delta, that are distinguished by the clonotype-specific chains in their T cell antigen receptors (TCRs). In another study, members of the laboratory demonstrated a fundamental difference in the subunit composition of the signal-transducing complexes of the alpha/beta and gamma/delta TCRs; a difference in TCR structure may influence the activation kinetics and functional responses of these distinct T cell lineages. A third area of investigation centered on studying the molecules that control T cell migration and trafficking, demonstrating a role for the chemokine receptor CCR9 in regulating homing of T cell progenitors to the thymus and their migration within the thymus during development.

The Unit on Genomic Imprinting, led by Karl Pfeifer, works on the regulated expression and biological function of a cluster of genes on the distal end of mouse chromosome 7. These genes share an unusual form of gene regulation, genomic imprinting, that is specific to mammalian organisms. Imprinted genes are expressed from only one chromosome in a parent-of-origin–dependent manner. The research group has focused on identifying the epigenetic markers that distinguish maternal and paternal chromosomes and on understanding the mechanisms by which these markers result in monoallelic gene expression. The organization and regulated expression of these genes is well conserved in humans, and the syntenic region is associated with Beckwith Wiedemann syndrome, a developmental disorder, as well as with inherited cardiac arrhythmias. The unit has successfully established a mouse model for this heart condition and is using the mouse to understand how b-adrenergic signals might stimulate cardiac malfunction in humans.