Page 40 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
somitogenesis. I also will provide a progress report on unpublished work, including characterization of the FGF3 axis defect and
our work on determining the FGF responsive elements in downstream target genes.
Beddington Lecture
Hox genes and hindbrain patterning: A story in segments. Robb Krumlauf
Youngwook Ahn
Christof Nolte
Marina Yurieva
Bony DeKumar
. 1)
Stowers Institute, Kansas City, MO; 2) Department of Anatomy and Cell Biology,
Kansas University Medical School, Kansas City, KS.
The hindbrain is a highly conserved and complex co-ordination center in the vertebrate CNS. It forms the medulla, pons and
cerebellum which play crucial roles in regulating functions such as sleep, respiration and heart rate. During development regional
diversity in hindbrain is established through a process of segmentation which divides an anterior region of the neural tube into
seven morphological discrete domains, termed rhombomeres. This segmental organization is also critical for patterning of the
cranial neural crest which generates most of the bone and connective tissues of head and facial structures. The Hox family of
transcription factors is coupled to this process and genetic studies have demonstrated that they provide a molecular framework for
specifying the unique identities of hindbrain segments and facial structures. A goal of our group is to use genetic and genomic
approaches in the mouse and comparative studies in other vertebrates to understand the regulatory cascades associated with Hox
activity, which control hindbrain segmentation and early head development. We employ functional and regulatory studies in
mice, using transgenic assays in BACs containing the HoxB complex; targeted mutagenesis in the endogenous Hox clusters;
transcriptional profiling of individual rhombomeres and the genome-wide identification of Hox binding sites and target genes by
ChIP-seq to investigate the signaling pathways and transcriptional mechanisms that control Hox expression in developing
hindbrain segments. Our results reveal that retinoic acid signaling is directly implicated in early positioning of the anterior
boundaries of Hox expression and in modulating later dynamic changes in neural expression. Auto and cross-regulatory
interactions between Hox genes actively maintain segmental domains of Hox expression. We find that sharing of retinoid
responsive enhancers, long-range regulatory interactions and insulators govern how retinoids establish and modulate ordered
domains of Hox activity. Hox genes and retinoid signaling also play key roles in defining specific groups of neurons that underlie
the neural circuitry controlled by the hindbrain. Our genomic analyses have revealed that following the initial induction of Hox
genes by retinoids, they in turn modulate multiple aspects of retinoid metabolism and catabolism. These feedback loops are
important for controlling neurogenesis during hindbrain patterning.
Stem Cells and Germ Cells
Targeting developmental pathways in cancer cells and stem cells. Frederic J de Sauvage
Genentech Inc., So. San Francisco,
The Notch, Wnt and Hedgehog signaling pathways play critical roles during embryonic development. These factors modulate
proliferation or differentiation of numerous cell types and are also involved in the regulation of the self-renewal and/or
differentiation of embryonic and adult stem cells. It is however becoming increasingly clear that these pathways are involved in
tumorigenesis when reactivated in adult tissues through mutations or overexpression of pathway components. Aberrant
reactivation of the Hedgehog (Hh) pathway in adult tissues leads to the development of cancers such as basal cell carcinoma
BCC) and medulloblastoma is often the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED
SMO) mutations. NOTCH1 mutations are found in most T-cell acute lymphoblastic leukemias and activation of the WNT
pathway, often through APC (adenomatous polyposis coli) gene mutations, is observed in a majority of colon adenocarcinomas.
However all 3 pathways play a role in normal gut homeostasis and may be involved in some aspect of colon tumorigenesis. The
development of inhibitors targeting these pathways is therefore of the highest interest as illustrated by the recent approval of
vismodegib, a Hh pathway inhibitor for the treatment of advanced BCC. While targeting of the Wnt pathway has been more
challenging, new opportunities have emerged with the identification of Lgr5 as a stem cell marker overexpressed in colorectal
Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell of origin model for prostate
cancer heterogeneity. Zhu Wang
Antonina Mitrofanova
Sarah Bergren
Cory Abate-Shen
Andrea Califano
Michael Shen
. 1)
Departments of Medicine and Genetics and Development, Columbia University Medical Center, New York,
NY; 2) Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University