LABORATORY
OF MAMMALIAN GENES AND DEVELOPMENT
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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. Heiner Westphal’s
Section on Mammalian Molecular Genetics studies the molecular genetics
of embryonic development. Over the years, the section has carried out a
detailed functional evaluation of members of the LIM class of homeobox genes
(termed Lhx genes) during mouse development. In the course of recent
experiments, the group identified two novel classes of proteins encoded,
respectively, by the Ldb and Ssdp gene families. They are co-factors whose
interaction with the Lhx-encoded LIM-homeodomain factors and other
transcriptional regulators is essential for embryonic development. The
discovery has focused attention on the mechanism of context-specific
decisions exerted by transcriptional complexes in the developing organism.
Furthermore, the interaction of Lhx genes with regulators of the canonical
Wnt pathway has elicited the section’s interest in the Dkk family of Wnt
inhibitors. More recently, the section has added two genes, SLB and Satb2,
to the ongoing analysis of developmental regulators. Research
in the Section on Cellular and
Developmental Biology, led by Paul Love, focuses on T lymphocyte
development. 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. The
experiments also demonstrated that coordination of lymphocyte signaling
responses is essential for preventing inappropriate cell proliferation. In
another study, members of the section discovered a difference in the subunit
composition of the signal-transducing antigen receptor complexes (TCRs)
expressed on the two 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 area of investigation, centered on the molecules that control T cell
migration and trafficking, revealed a role for the chemokine receptor CCR9 in
regulating the migration of developing T cells to and within the thymus. The Section
on Genomic Imprinting, directed by Karl
Pfeifer, examines 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 that is specific to
mammals, namely, genomic imprinting. 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 is
responsible for marking the parental origin of this chromosomal region. These
epigenetic modifications are established during gametogenesis. Later, the
presence of the modifications drives a developmental program that induces
further changes that then cause allele-specific expression. Specifically, the
cis element induces a developmental program that silences expression
of the paternal copy of H19, a putative tumor suppressor gene. The element
also carries a methylation-sensitive transcriptional insulator whose activity
results in paternal-specific expression of the Igf2 and Ins2 genes. The
organization and regulated expression of the genes in this cluster are
conserved in humans, and mutations in the human genes are associated with the
developmental disorder Beckwith Wiedemann syndrome, with several types of
tumors, and with 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. |