Heiner Westphal, MD, Chief

The Laboratory of Mammalian Genes and Development (LMGD) generates gene-altered mice to study embryonic and adult stem cells, pattern formation, T cell development, and genomic imprinting.

Heiner Westphal's Section on Mammalian Molecular Genetics studies the molecular genetics of mammalian development. The group focuses on developmental controls exerted by LIM-homeodomain (LIM-HD) transcription factors that are encoded by individual members of the Lhx gene family. In the embryo and even in the adult, Lhx genes mediate the transit from the stem cell stage to a precursor stage that precedes terminal differentiation. In earlier experiments, the group determined the functions of several Lhx genes through loss-of-function analysis of knockout mice and described obligatory cofactors, encoded by Ldb and Ssdp genes that mediate Lhx gene function. More recently, the Section adopted regimens of Cre-mediated conditional mutation, originally developed in this laboratory, to ask more fine-tuned questions about the action of LIM-HD/co-factor complexes and their downstream Dkk targets as patterns form and organs are established in the developing mouse embryo.

Sohyun Ahn is a newly appointed tenure-track investigator who heads the Unit on Developmental Neurogenetics. Her group is interested in elucidating the cellular and genetic mechanisms underpinning neural stem cell specification and lineage decisions. Using advanced genetic approaches in mice, the Unit is currently investigating transcription factors involved in the sonic hedgehog signaling pathway and their effect on maintenance, proliferation, and differentiation of neural stem cells. The group is also developing a new in vivo system to analyze the formation of neural circuits by adult-generated neurons in the hippocampal dentate gyrus in order to understand the elusive role of adult neurogenesis. Ahn's outstanding scientific contributions were recently acknowledged by a prestigious Presidential Early Career Award in Science and Engineering bestowed upon her by the President of the United States at a White House ceremony.

Research in the Section on Cellular and Developmental Biology, led by Paul Love, focuses on T lymphocyte development, particularly signal transduction molecules and pathways that regulate T cell maturation in the thymus. All mammals have two distinct lineages of T cells (designated alpha/beta and gamma/delta). The group's recent studies revealed a key difference in the subunit composition and signaling potential of the antigen receptors (TCRs) expressed on alpha/beta and gamma/delta T cells. The results also indicate that the distinct signaling potentials of the alpha/beta and gamma/delta TCR complexes play an important role in regulating alpha/beta versus gamma/delta lineage choice during early development. Another area of investigation, centered on molecules that control T cell migration and trafficking, demonstrated a critical function 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 regulated expression and biological function of a cluster of genes on the distal end of mouse chromosome 7. The genes in this cluster share an unusual form of transcriptional regulation called 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 called the ICR (for imprinting control region) whose epigenetic modifications, first established during gametogenesis, are responsible for marking the parental origin of the chromosomal region. The ICR carries a methylation-sensitive transcriptional insulator that is dependent on the DNA binding protein CTCF. As an insulator, the ICR organizes the chromosome across hundreds of kilobases in order to induce the appropriate promoter-enhancer associations necessary for gene transcription. The ICR also carries a methylation-dependent DNA silencer that is developmentally activated to affect the chromatin structure of nearby genes. Finally, the Section has established novel mouse models to address the biological role of several imprinted genes in normal cardiac function and specifically to understand the role of beta-adrenergic stress in regulating heart activity.