Heiner Westphal, MD, Chief

The Laboratory of Mammalian Genes and Development (LMGD) generates gene-altered mice to study stem cells, 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. The Section discovered two co-factors, Ldb1 and Ssdp1, that mediate the activity of Lhx genes. Current efforts are directed to analyzing the temporal and spatial controls exerted by the Lhx genes and their co-factors. In a separate study, the Section examines the function of Dkk genes that act as negative regulators of the canonical Wnt pathway. Another study has assigned Dkk2 a pivotal role in the maintenance of corneal epithelia during eye development. Finally, the Section has embarked on an ambitious pilot study aimed at reprogramming somatic cells to a state comparable to that of embryonic stem cells. To this end, somatic cells are fused with embryonic stem cells to generate hybrid cells that show characteristics of embryonic cells. The research is designed to seek a way to avoid the use of eggs as a source of reprogramming activity and thus bypass a host of ethical concerns about stem cell research.

The newly formed Unit on Developmental Neurogenetics is headed by Sohyun Ahn, a tenure-track scientist recruited from the Skirball Institute of Biomolecular Medicine, New York University. The primary goal of Dr. Ahn’s research is to elucidate the cellular and genetic mechanisms underpinning neural stem cell specification and lineage decisions. Specifically, she is pursuing the identification of novel gene(s) that mediate Sonic hedgehog (Shh) signaling in neural stem cells. In addition, she is investigating how Shh signaling regulates proliferation and/or differentiation of adult neural stem cells, using the mouse as a model system. A second goal of the Unit is to investigate how newly generated neurons, arising from adult stem cells, integrate into the existing neural circuits and contribute to plasticity of the hippocampus.

Research in the Section on Cellular and Developmental Biology, led by Paul Love, focuses on T lymphocyte development, with special emphasis on the role of signal transduction molecules and pathways. Recent laboratory 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. In the past year, the Section has shown that LAT-mediated signaling is required for thymocyte selection (the process by which developing T lymphocytes are induced to develop further or are deleted in accordance with the affinity of their antigen receptors for self peptides). In another study, members of the Section discovered a major 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. Using a flow cytometry–based assay, they recently resolved the stoichiometry of the gamma/delta TCR. In addition, results from a recent study indicate that the signaling potential of the gamma/delta TCR complex plays an important role in regulating alpha/beta versus gamma/delta lineage choice. Another area of investigation, centered on studying the molecules that control T cell migration and trafficking, demonstrated 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, led 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: 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 modifications, first established during gametogenesis, are responsible for marking the parental origin of this chromosomal region. The initial imprinting mark induces a developmental program of epigenetic modifications, including differential DNA methylation and histone modification, that in turn induces altered three-dimensional organization of the maternal and paternal chromosomes and results in their differential gene expression patterns. Mutations in the human syntenic genes are associated with various tumors and cardiac arrhythmias. The Section has established mouse models for the cardiac deficiencies by generating point mutations in the Kcnq1 locus. The analyses demonstrate that the underlying problem is an inability of the mutant heart to respond to beta-adrenergic stimulation.